The findings led to FDA approval for this indication

The PARP inhibitor niraparib demonstrated substantial benefits when used as maintenance therapy following complete or partial response to chemotherapy for advanced ovarian cancer among patients with multiple different biomarkers. These findings led the United States Food and Drug Administration (FDA), on April 29, 2020, to approve niraparib for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.

As has been previously reported, the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial demonstrated a hazard ratio (HR) for progression-free survival (PFS) of 0.43 (95% CI 0.31-0.59) with niraparib maintenance therapy following a response to platinum-based chemotherapy for advanced ovarian cancer among patients with homologous recombination deficient (HRd) disease. In an intent-to-treat analysis, niraparib therapy was also associated with a longer PFS in the overall population (HR 0.62; 95% CI 0.50-0.76) as well as in patients with BRCA mutations (HR 0.40; 95% CI 0.27-0.62), patients who were BRCA wild type (HR 0.50; 95% CI 0.31-0.83), and patients who were homologous recombination proficient (HRp) (HR 0.68; 95% CI 0.49-0.94).

Lead author Bradley J. Monk, MD, newly reported during a Society of Gynecologic Oncology (SGO) webinar that niraparib therapy also resulted in a longer PFS among patients with either BRCA1 mutations (HR 0.39; 95% CI 0.23-0.66; P < 0.0064) or BRCA2 mutations (HR 0.35; 95% CI 0.15-0.84). In addition, PFS was significantly longer with niraparib among HRd patients who were either BRCA wild type (HR 0.50; 95% CI 0.31-0.83) or who had BRCA mutations (HR 0.40; 95% CI 0.27-0.62). Monk is from Arizona Oncology (US Oncology Network), University of Arizona College of Medicine, and Creighton University School of Medicine, Phoenix.

“We have known for a while that we think, at least historically, that BRCA1 patients don’t do as well even with PARPs, and [these data] dispels that a bit,” Thomas J. Herzog, MD, of the University of Cincinnati Cancer Center in Cincinnati, Ohio, said in a comment on the study during the SGO webinar. “We see that the hazard ratios are very close, and it’s highly effective in both subgroups.”

The findings were to be presented at the SGO 2020 annual meeting, planned to take place in Toronto, Canada, from March 28 to 31. The conference was cancelled due to the Covid-19 pandemic, but a series of webinars of several studies intended to be presented at the conference were subsequently made available. Monk’s webinar took place on April 29, 2020.

“I have been a passionate advocate for maintenance treatment and against surveillance among patients [with ovarian cancer] at high risk of recurrence,” Monk said during the webinar. In an interview with BreakingMED, he explained that he has long been working on identifying better maintenance options for patients. First, he and colleagues demonstrated that 12 versus 3 months of paclitaxel maintenance resulted in an increased PFS of 7 months. But toxicity rates were high, so he moved to bevacizumab, demonstrating a 4-month improvement in PFS. “But that wasn’t very much, there were no biomarkers, and intravenous therapy is not that convenient. So, that’s when we started with the PARP agents,” he said.

This research led to FDA approval of niraparib in the maintenance setting. “It’s a broad approval in all biologic subtypes and for all patients with advanced ovarian cancer, as long as they respond,” said Monk. “It changes the world… Patients who have an HRd molecular signature will get a PARP inhibitor, niraparib… The reality is that, in many patients, [HRd status] will still be unknown because the tests are not widely done. But those patients should also get a PARP inhibitor. Even in the absence of a molecular signature, there might be an opportunity for clinical benefit… I think testing will become more common, but there is no question that PARP use will become more common.”

For the double-blind, international, phase III PRIMA/ENGOT-OV26/GOG-3012 study, 733 patients with newly diagnosed advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete or partial response to first-line platinum-based chemotherapy were randomized to receive niraparib (n = 487) or placebo (n = 246) once daily for 36 months or until disease progression. Patient responses were stratified by best response to first-line chemotherapy, receipt of neoadjuvant chemotherapy, and homologous recombination status (deficient/proficient/not determined). The primary endpoint of the study was PFS, as assessed by a blinded independent central review, overall and based on homologous recombination status.

Overall, 373 patients (51%) were HRd, including 247 of those who received niraparib and 126 of those who received a placebo. Another 249 (34%) were HRp (169 on niraparib and 80 on placebo). A total of 35% of participants had stage IV disease, 67% had received neoadjuvant chemotherapy, and 31% had a partial response to first-line chemotherapy.

There were no new safety signals to report in this update of the study. The most commonly reported grade ≥ 3 adverse events with niraparib were anemia (31%), thrombocytopenia (29%), reduced platelet count (13%), and neutropenia (13%).

“It works in all-comers, but it works the best in BRCA, and then the next best in HRd, and it still works a little bit in HRp,” said Monk.

“I think what’s great about these three trials [PRIMA, PAOLA-1, and VELIA] is that they really give our patients new treatments, new options, and renewed hope,” said Herzog. “Now, niraparib was approved in the frontline setting.”

  1. Niraparib improved progression-free survival in patients with advanced ovarian cancer who are homologous recombination status deficient and proficient, who have BRCA1 or BRCA2 mutations, and who are both homologous recombination deficient and have BRCA mutations.

  2. The best responses were seen in patients with BRCA mutations who were homologous recombination status deficient, but the drug is now approved regardless of biomarker status.

Alison Palkhivala, Contributing Writer, BreakingMED™

The PRIMA/ENGOT-OV26/GOG-3012 study was sponsored by Tesaro, Inc.

Monk reports consulting for and receiving honoraria/reimbursement and/or speaker’s bureau(s) and/or being a stockholder/shareholder from ImmunoGen, Oncosec, ChemoID, Agenus, Oncomed, Mateon (formally Oxigene), Precision Oncology, Amgen, Asymmetric Therapeutics, VBL, Pfizer, Oncoquest, Clovis, Aravive, Immunomedics, Incyte, Vigeo, Mersana, Roche/Genentech, Merck, Conjupro, Myriad, GOG Foundation, Takeda, ChemoCare, Nucana, Puma, AstraZeneca Consulting, Laekna Health Care, Perthera, Abbvie, Advaxis, TESARO/GSK, Regeneron, Geistlich, Janssen/Johnson&Johnson, Eisai, Genmab/Seattle Genetics, Circulogene, Boston Biomedical, and Samumed.

Herzog reports being on advisory boards for and/or receiving honoraria/reimbursement from Genentech, Caris, Tesaro, Clovis, Johnson&Johnson, and AstraZeneca.

Cat ID: 445

Topic ID: 78,445,730,445,692,357,693,192,356