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Medical Director & Program Leader
Dana-Farber Cancer Institute
Professor of Medicine
Harvard Medical School
Ursula Matulonis, MD, has disclosed that she has received consulting fees and other financial or material support from Merck.
In 2020, the FDA and EMA approved the PARP inhibitor niraparib as a first-line maintenance treatment for patients with advanced ovarian cancer who have responded to platinum-based chemotherapy. The decision was based on data from the phase III PRIMA clinical trial published in the New England Journal of Medicine and presented at the European Society of Medical Oncology meeting in September 2019. In this ClinicalThought, I discuss the clinical implications of the approval of niraparib for patients newly diagnosed with advanced ovarian cancer.
PRIMA (PRIMA/ENGOT-OV26/GOG-3012) is an ongoing, double‑blinded phase III study that randomized 733 women with advanced and high-risk serous ovarian cancer 2:1 to maintenance therapy with niraparib or placebo following initial platinum-based chemotherapy. All of the enrolled women had at least a PR to first-line platinum‑based chemotherapy and had stage III (65%) or stage IV (35%) ovarian cancer. Among those women with stage III disease, all of them were at high-risk of recurrence due to inoperable tumors or residual tumors following debulking surgery (23.1%). Patients were stratified by homologous recombination deficiency (HRD) score, clinical response to first-line chemotherapy, and receipt of neoadjuvant chemotherapy. The primary endpoint of PRIMA was PFS (in both the overall and HRD population), and secondary endpoints are OS, PFS2, and quality of life.
Patients initially received 300 mg/day of niraparib, but partway through the trial the dosing was adjusted based on patient weight and platelet count. The NOVA study, which enrolled patients with platinum-sensitive, recurrent ovarian cancer, had found that 200 mg/day of niraparib reduced adverse events in patients who weighed < 77 kg and/or whose platelet counts were < 150 000/µL. Ultimately, 70% of participants in the PRIMA trial had their dose reduced. Patients were treated for 36 months or until cancer progression.
In the overall patient population, the median PFS was 13.8 months for niraparib vs 8.2 months for placebo, with an HR of 0.62. Patients with HRD and BRCA mutations had an HR of 0.4 and a median PFS of 22.1 months vs 10.9 months in favor of niraparib. Patients with HRD but who were BRCA wild type also benefited from niraparib, with an HR of 0.5 and a median PFS of 19.6 months vs 8.2 months. Patients who were homologous recombination proficient (HRP) and BRCA wild type also had some benefit, with median PFS of 5.4 months with placebo vs 8.1 months with niraparib. However, the HR was 0.68, indicating that patients with HRD have a greater benefit from PARP inhibitors.
Clinical Implications: My Thoughts
With the recent approval of niraparib as maintenance therapy for patients with advanced ovarian cancer who are in CR or PR to frontline platinum-based chemotherapy, we now have a few different PARP inhibitor options in this setting: niraparib, which is approved regardless of BRCA mutations or HRD status, olaparib monotherapy for patients with BRCA mutations, and the combination of olaparib plus bevacizumab for patients with HRD (either BRCA mutation or genomic instability); all of these options mandate upfront responsiveness of the cancer to platinum-based chemotherapy.
All patients with newly diagnosed ovarian cancer, regardless of stage, family history, histology, and patient age, should undergo germline genetic testing at the time of initial diagnosis because of the implications for family members and the patients themselves. For patients with newly diagnosed ovarian cancer, in addition to germline testing, I also perform somatic testing; this is particularly important for patients with high-grade serous ovarian cancer, since not only will 16% have a germline BRCA1/2 mutation and but 6% of patients will also have cancers that harbor a somatic BRCA1/2 mutation. In addition to examining BRCA1/2, somatic analysis will also test for other genes implicated in the risk of ovarian cancer, such as RAD51C, RAD51D, and others. In 2020, ASCO published important guidelines for Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer.
I find HRD testing helpful for BRCA wild-type patients whose high-grade serous ovarian cancer responds to initial platinum-based chemotherapy. HRD testing helps me and these patients decide whether they should receive a PARP inhibitor because the benefit of PARP inhibitors is greater in patients whose cancers are HRD vs HRP. I base my decisions on which PARP inhibitor to use and in which clinical settings based on the published clinical trials and current FDA approvals. As observed in trials testing PARP inhibitors in both the newly diagnosed and recurrent settings, PARP inhibitors have their greatest benefit in BRCA-mutated cancers that are rich in HRD, next in HRD but BRCA wild-type cancers, and finally the least benefit, although some present in the HRP, BRCA wild-type cancers. I believe that the use of a PARP inhibitor as maintenance is standard of care in women with BRCA-mutated cancers who are in response to platinum-based chemotherapy. On the other end of the spectrum of homologous recombination status, the decision to use a PARP inhibitor in patients with HRP, BRCA wild-type cancers should be based on a careful risk-to-benefit discussion with the patient, also taking into account her comorbidities.
On Monday, December 14, 2020, along with my colleagues Antonio González-Martin, MD, PhD, and Ignace Vergote, MD, PhD, I gave a talk titled, “Precision Medicine in Ovarian Cancer: Understanding the Evolving Role of PARP Inhibitors” at the European Society of Gynaecological Oncology annual meeting. Please enjoy the on-demand Webcast and downloadable slides here.
How has the recent approval of niraparib for advanced ovarian cancer changed your clinical practice? Please answer the polling question and share your thoughts in the comment box below!