Analyses Underscore Extent of Frontline Maintenance Niraparib Benefit in Ovarian Cancer

Dana Chase, MD

The success of frontline maintenance niraparib (Zejula) in the phase III PRIMA trial (ENGOT-OV26/GOG-3012) extends to meeting biomarker-defined and other secondary endpoints and showing positive patient-reported outcomes (PROs), according to 3 analyses reported as part of the virtual platform for the SGO 2020 Annual Meeting.

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.

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.

Biomarkers: BRCA and 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 tumors, 169 received niraparib and 80 received placebo.

The biomarker analysis reported through the SGO platform determined that the statistically significant and clinically meaningful PFS benefit observed with niraparib in the overall population also extended to all biomarker-defined subgroups.³

Among the HRD cohort, the HR for PFS was 0.43 (95% CI, 0.310-0.588; P <.0001), and in the homologous recombination—proficient group, the HR was 0.68 (95% CI, 0.492-0.944; P = .0203).

In patients with BRCA mutations, the HR for PFS was 0.40 (95% CI, 0.265-0.618; P <.0001) and in the BRCA—wild-type population, the HR was 0.50 (95% CI, 0.305-0.831; P = .0064).

Secondary Endpoints: TFST and PFS2

A second analysis shared through SGO showed that in the overall population, the median time to first subsequent therapy (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).⁴

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 homologous recombination—proficient 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 homologous recombination—proficient (HR, 0.56; 95% CI, 0.34-0.91) populations.

Patient-Reported Outcomes

The third analysis shared as part of the 2020 SGO platform was a report of PROs from the PRIMA trial.⁵

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 OncLive.

“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.”

Next Up for Niraparib

Based on the PRIMA findings, the FDA accepted a supplemental New Drug Application in February 2020 for niraparib for use as a frontline maintenance treatment for women with advanced ovarian cancer who responded to platinum-based chemotherapy regardless of biomarker status.⁶

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/μL. 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 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.

References

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). Presented at: ESMO Congress 2019, Barcelona, Spain, September 27 to October 1, 2019. LBA 1.
2. Gonzalez-Martin A, Pothuri B, Vergote I, et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. [published online September 28, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1910962
3. Monk BJ, Gonzalez-Martin A. Efficacy of niraparib therapy in patients with newly diagnosed advanced ovarian cancer by BRCA and homologous recombination status: PRIMA/ENGOT-OV26/GOG-3012 study. Data made available as part of the virtual platform for the SGO 2020 Annual Meeting. Abstract 31.
4. Han SN, Monk BJ, Gonzalez-Martin A. Time to first subsequent therapy (TFST) and progression-free survival 2 (PFS2) from the phase 3 randomized, double-blind PRIMA/ENGOT-OV26/GOG-3012 study in patients with newly diagnosed ovarian cancer. Data made available as part of the virtual platform for the SGO 2020 Annual Meeting. Abstract 32.
5. Pothuri B, Chase DM, Monk BJ, and Gonzalez Martin A, et al. Patient-reported outcomes (PRO) in patients receiving niraparib in the PRIMA/ENGOT-OV26/GOG-3012 trial. Data made available as part of the virtual platform for the SGO 2020 Annual Meeting. Abstract 83.
6. U.S. FDA accepts GSK’s sNDA application for Zejula (niraparib) for first-line maintenance treatment for women with platinum-responsive advanced ovarian cancer. Published February 24, 2019. https://bit.ly/38UuuMh. Accessed April 10, 2020.