Brian Slomovitz, MD
Professor, Florida International University
Gynecologic Oncology, Broward Health
Efficacy of niraparib by timing of surgery and residual disease: a post hoc analysis of patients in the PRIMA/ENGOT-OV26/GOG-3012 study
O’Cearbhaill R, Pérez-Fidalgo J-A, Monk BJ, et al. Poster presented at: Society of Gynecologic Oncology 2021 Virtual Annual Meeting, March 19-25, 2021. Poster 10381.
Niraparib efficacy in newly diagnosed advanced ovarian cancer by surgical timing and residual disease status shows highest efficacy in hardest to treat: A post-hoc analysis
Niraparib, an oral PARP inhibitor, is approved as maintenance therapy for patients with newly diagnosed and recurrent, platinum sensitive ovarian cancer after platinum-based chemotherapy. The PRIMA trial showed a significantly longer progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer, regardless of homologous-recombination deficiency (HRD) status. A post hoc analysis of the PRIMA trial looked into the efficacy of niraparib maintenance therapy after primary debulking surgery (PDS) and neoadjuvant chemotherapy/ interval debulking surgery (NACT/IDS). This study was presented at the Society of Gynecologic Oncology 2021 Virtual Annual Meeting.
The PRIMA trial was conducted in patients with newly diagnosed, advanced, high-grade serous or endometroid ovarian, primary peritoneal, or fallopian tube with complete or partial response to the first-line platinum-based chemotherapy. All the patients had stage III or IV high-grade serous or endometrioid cancer and all received six to nine cycles of chemotherapy. Patients were required to have a complete or partial response prior to the enrollment in the study. The patients were randomly assigned in a 2:1 ratio to receive oral 200 or 300 mg daily niraparib (based on the weight and platelet count) or placebo once daily in 28-day cycles for 36 months or until disease progression. All the tumors were evaluated for HRD status using Myriad MyChoice CDx next generation sequencing. The primary end point of the study was PFS which tested hierarchically, first in patients with HRD tumor and then in overall population. The post hoc analysis investigated the efficacy of niraparib, measuring PFS, based on time of surgery, either PDS or IDS/NACT and postoperative residual disease status, which was defined as no visible residual disease (NVRD) or residual visible disease (VRD).
In the overall population, the median progression-free survival (mPFS) was 13.8 in niraparib group versus 8.2 months in placebo group. By surgical status alone, in PDS group, the patients who received niraparib had a mPFS of 13.7 months versus 8.2 months in placebo group (HR, 0.67; 95% CI, 0.468-0.964). In IDS group, patients had a mPFS of 14.2-month on niraparib and 8.2 months on placebo (HR, 0.57; 95% CI, 0.441-0.731).
The mPFS in this post hoc analysis in those who had PDS with VRD was 11.8 in patients who received niraparib compared to 7.8 months in patients on placebo (hazard ratio [HR], 0.58; 95% CI, 0.391-0.864). The mPFS in the IDS with NVRD group was 18.2 versus 10.9 months (HR, 0.65; 95% CI, 0.461-0.91) and in the IDS with VRD was 11.1-months versus 5.6 months (HR, 0.41; 95% CI, 0.269-0.620).
The highest reduction in risk of progression was in patients with IDS and VRD (59%), followed by a 42% reduction in risk of progression in patients who received PDS and had VRD and a 35% reduction in patients with IDS and NVRD. The number of patients with PDS and NVRD were too small to result a meaningful clinical conclusion (n=37). The PFS were similar in niraparib vs placebo across PDS and IDS groups.
Treatment of advanced ovarian cancer is an ongoing challenge. Maintenance therapy, with either bevacizumab or PARP inhibitions (PARPi), has shown significant increases in PFS leading to FDA approval of these agents. Recent groundbreaking clinical trials hold promises for treatments with longer PFS and a more tolerable safety profile. PARPi are the new line of cancer treatment drugs that have revolutionized the treatment of ovarian cancers in particular. The PRIMA trial showed that among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer PFS than those who received placebo, regardless of homologous-recombination deficiency. In this post hoc analysis of the PRIMA trial, the hardest to treat patients (IDS with VRD) showed the highest reduction in risk of progression in those who received niraparib. In addition, the impact of niraparib on extending PFS was seen across all surgical subgroups.
The multi-functional enzyme Poly ADP ribose polymerase (PARP) plays a critical and complex role in DNA repaid to maintain the genome stability. The commonly accepted hypothesis is that the PARPi disrupt the second DNA repair pathway in HR deficient cancer cells and accumulation of DNA damage induces cell death via apoptosis. However, the exact mechanism of action of PARPi is not known and there are studies that disagree with this hypothesis.
Could this explain the efficacy of niraparib even in HR proficient ovarian cancers? The fact is that better understanding the function of PARP in DNA repair would possibly broaden its implication in cancer treatment. Until then, additional studies need to be done that would further elucidate the clinical application of these relatively safe drugs.
Dr. Bradley Monk, the senior investigator of the PRIMA trial highlighted, “The post hoc analysis adds even more confidence to the idea that every patient with newly diagnosed advanced ovarian cancer responding to first-line platinum-based therapy needs maintenance treatment with a PARPi such as niraparib. This is consistent with the NCCN and ASCO guidelines.”