Following its success in the phase III PRIMA study, frontline niraparib maintenance demonstrated positive patient-reported outcomes, as well as met biomarker-defined and other secondary endpoints, according to 3 analyses to be reported as part of the Society of Gynecologic Oncology 2020 Annual Meeting.
Following its success in the phase III PRIMA (ENGOT-OV26/GOG-3012) study, frontline niraparib (Zejula) maintenance demonstrated positive patient-reported outcomes (PROs), as well as met biomarker-defined and other secondary end points, according to 3 analyses reported in a webinar as part of the Society of Gynecologic Oncology (SGO) 2020 Virtual Annual Meeting I.
The phase III PRIMA study randomized 733 patients with stage III/IV ovarian cancer who responded to first-line platinum-based chemotherapy in a 2:1 ratio to receive maintenance niraparib (n = 487) or placebo (n = 246).1,2 Patients were randomized within 12 weeks of finishing the last cycle of chemotherapy. The study met the primary outcome measure of progression-free survival (PFS), showing that frontline maintenance niraparib improved median PFS by 5.6 months compared with placebo in the overall population.
The 3 analyses presented through the SGO platform demonstrated how this benefit was observed regardless of homologous recombination–deficient (HRD) or BRCA mutation status, and was also demonstrated through several key secondary outcomes measures.
"Patients with the highest risk of early disease progression can benefit significantly and statistically [with niraparib]," said Bradley J. Monk, MD, during the SGO webinar when presenting new findings from the PRIMA trial.
At the time of the SGO webinar, the FDA approved niraparib as first-line 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.3
Biomarkers:BRCAand HRD Status
HRD and BRCA status were key biomarkers evaluated in the trial. Of the 733 patients randomized, 373 had tumors that were HRD, of whom 247 received niraparib and 126 received placebo. Among the 249 patients with homologous recombination–proficient (HRP) tumors, 169 received niraparib and 80 received placebo.
The biomarker analysis determined that the statistically significant and clinically meaningful PFS benefit observed with niraparib in the overall population also extended to all biomarker-defined subgroups.4
Among the HRD cohort, by blinded independent central review, the median PFS with niraparib was 21.9 months (95% CI, 19.3-NE) compared with 10.4 months (95% CI, 8.1-12.1) with placebo, representing a 57% reduction in the risk of relapse or death (HR, 0.43; 95% CI, 0.310-0.588;P<.0001). At 12 months, the PFS rate with niraparib was 72% and 59% at 18 months, compared with 42% and 35%, respectively, with placebo.
Among patients with HRD and BRCA-mutant tumors, the hazard ratio (HR) was 0.40 (95% CI, 0.27-0.62) compared with 0.50 (95% CI, 0.31-0.83) in patients with BRCA wild-type and HRD tumors. In the HRP group, the HR was 0.68 (95% CI, 0.492-0.944; P = .0203).
Efficacy with niraparib was also similar in patients with BRCA1 and BRCA2 mutations. In patients with BRCA1 mutations, the HR for PFS was 0.39 (95% CI, 0.23-0.66), and in those with BRCA2 mutations, the HR was 0.35 (95% CI, 0.15-0.84).
Individualizing Treatment and Its Effect on Adverse Events
There were no new safety signals observed in the PRIMA trial, the safety profile was consistent with previous niraparib trials. The rate of dose interruptions was also similar with prior reports for niraparib.
The most common any-grade adverse events (AEs) with niraparib were anemia (63%), nausea (57%), thrombocytopenia (46%), constipation (39%), and fatigue (35%). Common grade ≥3 AEs included anemia (31%), thrombocytopenia (29%), platelet count decrease (13%), and neutropenia (13%).
Of note, treatment discontinuation due to thrombocytopenia was reported in 4.3% of patients, but there were no treatment-related deaths on the study. One patient in the niraparib arm, however, did develop myelodysplastic syndrome after 9 months of treatment.
In the SGO webinar, Monk also noted that the rate of grade ≥3 hematologic treatment-emergent AEs was reduced in patients who received an individualized dose of niraparib rather than a fixed dose.
For example, the rate of grade ≥3 thrombocytopenia was 36% with the fixed dose and 15% with the individualized dose. Grade ≥3 anemia was reported in 36% versus 23% with the fixed and individualized doses, respectively. Platelet count decrease of grade ≥3 was reported in 16% who received the fixed dose and in 7% who received an individualized dose. Neutropenia of grade ≥3 was observed in 15% and 10% in those who received the fixed and individualized doses, respectively.
A second analysis shared by Sileny Han, MD, during the SGO webinar showed that the time to first subsequent therapy (TFST) and second PFS (PFS2), both secondary end points of the trial, were improved in all patients treated with niraparib.
The median TFST was 18.6 months (95% CI, 15.8-24.7) with niraparib versus 12.0 months (95% CI, 10.3-13.9) with placebo (HR, 0.65; 95% CI, 0.52-0.80; P = .0001).5
In patients with tumors that were HRD, the median TFST was not yet reached in patients receiving niraparib, compared with 13.7 months in the placebo arm (HR, 0.46; 95% CI, 0.33-0.64; P <.0001). Among patients with HRP tumors, the median TFST was 11.6 months versus 7.9 months in the niraparib (n = 169) and placebo (n = 80) arms, respectively (HR, 0.64; 95% CI, 0.46-0.90; P <.0105).
The available results for PFS2 were at 20% data maturity in the overall population. The HR for PFS2 favored the niraparib arm in the overall (0.81; 95% CI, 0.58-1.14), HRD (HR, 0.84; 95% CI, 0.49-1.45), and HRP (HR, 0.56; 95% CI, 0.34-0.91) populations.
Overall, 37% of patients were still receiving niraparib at cutoff versus 28% in the placebo arm.
Han, of the Departments of Obstetrics and Gynecology, University Hospital Leuven, noted that a higher proportion of patients in the placebo arm received subsequent therapy compared with those in the niraparib group.
Interim findings for overall survival (OS) favored niraparib over placebo in all subgroups. In the overall population, the rate of OS at 2 years was 84% with niraparib versus 77% with placebo (HR, 0.70; 95% CI, 0.44-1.11). In patients with HRD tumors, the rate at 2 years was 91% with niraparib versus 85% with placebo (HR, 0.61; 95% CI, 0.27-1.39), and the rates were 81% and 59% (HR, 0.51; 95% CI, 0.27-0.97), respectively, for those with HRP tumors.
Updated findings for these end points at full maturity are expected to be presented at a future meeting.
The third analysis shared as part of the 2020 SGO platform was a report of PROs from the PRIMA trial.6
For the secondary endpoint of PROs, the investigators collected the information during the treatment period every 8 weeks for 56 weeks and then every 12 weeks thereafter. For patients discontinuing treatment, PROs were collected at the time of discontinuation, and then at 4, 8, 12, and 24 weeks (+1 week for each timepoint), regardless of the status of subsequent treatment.
The PRO instruments used by the investigators were FOSI, EQ-5D-5L, EORTC-QLQ-C30, and EORTC-QLQ-OV28.
The researchers determined that health-related quality-of-life scores were similar between the niraparib and control arms, based on the EORTC-QLQ-C30 and EORTC-QLQ-OV28. At each timepoint, the mean scores were comparable between the 2 study arms.
"Quality-of-life changes with maintenance niraparib are not significant [in PRIMA]," study investigator Dana Chase, MD, FACOG, assistant professor at the University of Arizona College of Medicine Phoenix and Creighton University at St. Joseph's Hospital and Medical Center, Arizona Oncology, The US Oncology Network, said in an interview with Targeted Oncology.
"With a PARP inhibitor, you have most of your side effects in the first couple of months on therapy. We have really good data from PRIMA for the first couple months of therapy showing that quality of life is not affected" said Chase, adding, "What was also interesting about the data is that certain symptoms, such as fatigue, got better as patients continued their niraparib therapy.... [At baseline] the fatigue was comparable [between the niraparib and placebo arms] and then actually got better than placebo throughout the maintenance period."
Overall for Niraparib
In the overall population of the PRIMA study, the median PFS in the niraparib arm was 13.8 months compared with 8.2 months in the placebo group, representing a 38% reduction in the risk of progression or death with the PARP inhibitor (HR, 0.62; 95% CI, 0.50-0.76;P<.001).
At the initiation of the study, niraparib was given at a fixed dose of 300 mg, which was adjusted to include a lower dose of 200 mg for those weighing less than 77 kg and for those with platelet counts below 150K/muL. The median relative dose intensity in the study was 63%. Gonzalez-Martin noted that future presentations would focus on the potential impact of this dose change.
Patient characteristics were similar across groups. The ECOG performance status was 1 for approximately 70% of patients, two-thirds had a FIGO stage of III, and a third had stage IV disease. The primary tumor locations were the ovary, fallopian tube, and peritoneum. The majority of patients had serous histology (~95%). Most patients had achieved a complete response to prior chemotherapy (70%). Two-thirds of patients received neoadjuvant chemotherapy, and none received bevacizumab, as the study was designed prior to approval of the VEGF inhibitor in the frontline setting.
At the interim analysis, median overall survival (OS) was not yet reached, at just 10.8% data maturity. At this early time point, however, the 24-month OS rate in the full population was 84% in the niraparib group and 77% in the placebo arm (HR, 0.70; 95% CI, 0.44-1.11).
More patients experienced treatment-related adverse event (AE) of any grade in the niraparib arm compared with placebo (96.3% vs 68.9%). Grade ≥3 treatment-related AEs were experienced by 65.3% of patients in the niraparib arm compared with 6.6% of those in the placebo group. The most common AEs of grade ≥3 severity in the niraparib and placebo groups, respectively, were anemia (31.0% vs 1.6%), thrombocytopenia (28.7% vs 0.4%), platelet count decrease (13.0% vs 0%), and neutropenia (12.8% vs 1.2%).
Overall, 70.9% of patients required a dose reduction in the niraparib arm, and 12% of patients discontinued therapy due to AEs. The main AEs relating to discontinuation were myelosuppressive in nature, with 4.3% from thrombocytopenia.
Niraparib monotherapy is also approved as a maintenance therapy in the recurrent ovarian cancer setting. The PARP inhibitor is also approved for the treatment of patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with ≥3 prior chemotherapy regimens, and whose cancer is associated with HRD status.