Making sense of maintenance therapy in advanced ovarian cancer has been a tall order since the publication of impressive data for not one but three poly (ADP-ribose) polymerase (PARP) inhibitors at the European Society for Medical Oncology (ESMO) 2019 Congress.1 The picture became a little clearer on April 29, 2020, however, when the U.S. Food and Drug Administration (FDA) approved the PARP inhibitor niraparib for maintenance treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are complete or partial responders to first-line platinum-based chemotherapy.2
“I’ve been a passionate advocate for maintenance treatment of patients at high risk of recurrence and against surveillance.”— Bradley J. Monk, MD
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During the 2020 Annual Meeting on Women’s Cancer Webinar Series produced by the Society of Gynecologic Oncology (SGO), Bradley J. Monk, MD, presented updated data from the pivotal PRIMA trial (ClinicalTrials.gov identifier NCT02655016), which randomly assigned 733 patients to niraparib or matched placebo.3
“I’ve been a passionate advocate for maintenance treatment of patients at high risk of recurrence and against surveillance,” said Dr. Monk, Professor of Obstetrics and Gynecology at the University of Arizona College of Medicine, Phoenix. “These data once again show that patients with the highest risk of early disease progression can benefit from niraparib, and there were no new safety signals.”
Clinical Benefit in Subgroups
Although findings presented by Dr. Gonzalez-Martin at the ESMO 2019 Congress demonstrated benefit across biomarker subgroups after first-line platinum-based chemotherapy, Dr. Monk shared additional exploratory analysis of homologous recombination–deficient (HRD) and homologous recombination–proficient (HRP) subgroups. These hypothesis-generating data showed that niraparib improved progression-free survival in both HRD (BRCA-mutant and BRCA wild-type) and HRP disease.
“We recognize that BRCA1 mutations are about twice as common as BRCA2 mutations, and more pathogenic, and patients with BRCA1 mutations have been historically more difficult to treat with PARP inhibition,” said Dr. Monk. “This analysis showed a consistent treatment effect in both patients with BRCA1 and BRCA2 mutations, which is an important new piece of information.”
As Dr. Monk reported, PRIMA was designed to address an unmet need in the first-line treatment of advanced ovarian cancer. The trial included patients with high-grade serous or intermediate-grade stage III or IV cancer with residual disease after primary debulking surgery or those who received neoadjuvant chemotherapy. Patients who underwent primary debulking surgery with complete cytoreduction were excluded from the analysis. Of the 733 patients enrolled on study, 50% had HRD-positive disease. Patients were randomly assigned to receive niraparib or placebo.
Analysis showed a benefit in progression-free survival regardless of the presence or absence of HRD, said Dr. Monk. However, the benefit was greatest in HRD-positive patients (hazard ratio [HR] = 0.43; 95% confidence interval [CI] = 0.31–0.59; P < .001). HRD-positive patients with BRCA-mutated disease and BRCA wild-type disease had a hazard ratio of 0.40 (95% CI = 0.27–0.62) and 0.50 (95% CI = 0.31–0.83), respectively. Patients with HRP disease had a hazard ratio of 0.68. (95% CI = 0.49–0.94).
On April 29, 2020, the FDA approved niraparib for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy.
An individualized dosing regimen, which was introduced for the final third of patients enrolled on study, also significantly reduced high-grade hematologic toxicities, according to Dr. Monk. The rate of grade ≥ 3 thrombocytopenia fell from 36% to 15% with personalized dosing. As Dr. Monk reported, the FDA-approved dose for first-line maintenance treatment of advanced ovarian cancer is based on body weight or platelet count.
Sileny Han, MD, PhD, of the Department of Obstetrics and Gynecology, University Hospitals Leuven, Belgium, also reported that treatment benefits persist beyond the first disease progression.4 “Analysis of the time to first subsequent therapy showed significant advantages in favor of niraparib, and this was seen in the overall population as well as in those with HRD and HRP tumors,” said Dr. Han.
Sileny Han, MD, PhD
The rate of second progression-free survival, defined as randomization to the time of disease progression on second-line treatment, also favors niraparib maintenance versus placebo, with a benefit seen in all biomarker subgroups, Dr. Han added. However, these results are not yet mature.
DISCLOSURE: Dr. Monk has received consulting fees, honoraria, and/or research funding from AbbVie, Advaxis, Agenus, Amgen, Array BioPharma, AstraZeneca, Cerulean Pharma, ChemoCare, ChemoID, Clovis Oncology, Conjupro Biotherapeutics, Eisai, Geistlich Pharma, Genentech, Genmab, GlaxoSmithKline, ImmunoGen, Immunomedics, Incyte, Janssen, Lilly, Mateon Therapeutics, Merck, Morphotek, Myriad Pharmaceuticals, Novartis, NuCana BioMed, OncoMed, OncoQuest, OncoSec, Perthera, Pfizer, Precision Oncology, Regeneron, Roche/Genentech, Samumed, Takeda, and VBL Therapeutics. Dr. Han reported no conflicts of interest.
1. Gonzalez-Martin A, Pothuri B, Vergote I, et al: Niraparib therapy in patients with newly diagnosed advanced ovarian cancer (PRIMA/ENGOT-OV26/GOG-3012 study). 2019 ESMO Congress. Abstract LBA1. Presented September 28, 2019.
2. U.S. Food and Drug Administration: FDA approves niraparib for first-line maintenance of advanced ovarian cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-niraparib-first-line-maintenance-advanced-ovarian-cancer. Accessed May 5, 2020.
3. Monk BJ, Han S, Pothuri B, et al: Efficacy of niraparib therapy in patients with newly diagnosed advanced ovarian cancer by BRCA and homologous recombination status: PRIMA/ENGOT-OV26/GOG-3012 study. 2020 Society of Gynecologic Oncology Annual Meeting. Webinar 2. Presented April 29, 2020.
4. Han S, Pothur B, Heitz F: Time to first subsequent therapy and progression-free survival 2 from the phase 3 randomized, double-blind PRIMA/ENGOT-OV26/GOG-3012 study in patients with newly diagnosed ovarian cancer. 2020 Society of Gynecologic Oncology Annual Meeting. Webinar 2. Presented April 29, 2020.
Thomas J. Herzog, MD
Thomas J. Herzog, MD, Deputy Director, University of Cincinnati Cancer Center, who presented a distillation of the PRIMA trial data along with updated results of the phase III PAOLA-1 trial of olaparib plus bevacizumab maintenance, called the data “practice-changing.”...