The final overall survival analysis of the phase III PRIMA trial found no survival benefit for maintenance niraparib over placebo in advanced ovarian cancer. However, the PARP inhibitor continued to exert a sustained progression-free survival benefit, investigators reported at the European Society for Medical Oncology (ESMO) Congress 2024.1
Antonio González-Martín, MD, PhD
Patients with newly diagnosed advanced ovarian cancer responding to front-line platinum-based chemotherapy were randomly assigned to maintenance therapy with niraparib or placebo. At a median follow-up of about 6 years, median overall survival was 46.6 months with niraparib and 48.8 months with placebo (hazard ratio [HR] = 1.01; P = .8834). The rate of progression-free survival at 5 years, however, remained higher with niraparib: 22% vs 12% with placebo (HR = 0.66; 95% confidence interval [CI] = 0.55–0.78), according to Antonio González-Martín, MD, PhD, of the Cancer Center Clínica Universidad de Navarra and Grupo Español de Investigación en Cancer Gynecológico, Madrid.
“A sustained progression-free survival benefit was observed with niraparib with additional follow-up in the overall and homologous recombination–deficient populations. Among patients who were alive at 5 years in the homologous recombination–deficient population, those who received niraparib were twice as likely to be progression-free as patients who received placebo: 35% vs 16%,” he reported. “Long-term data support the benefit of niraparib as first-line maintenance therapy regardless of homologous recombination–deficient status.”
Previous Analysis Led to Approval
PRIMA/ENGOT-OV26/GOG-3012 enrolled 733 patients with advanced high-grade serous or endometrioid ovarian cancer at high risk for recurrence; they were randomly assigned 2:1 after successful platinum therapy to niraparib or placebo for up to 3 years. Overall survival was analyzed at 60% maturity and was hierarchical, with the overall population tested first and then the homologous recombination–deficient population.
Previously, at a median follow-up of about 1.2 years, PRIMA met its primary endpoint of progression-free survival, both in the intention-to-treat group (HR = 0.62; P < .001) as well as in the homologous recombination–deficient population (HR = 0.43; P < .001),2 leading to U.S. Food and Drug Administration approval of niraparib maintenance. The final preplanned overall survival data were presented at the ESMO Congress 2024 along with updated ad hoc, investigator-assessed progression-free survival results.
Key Findings in Updated Analysis
The main long-term outcomes in the updated analysis are listed here, for the overall population and homologous recombination–deficient and –proficient subsets, for the niraparib arm vs placebo arm:
- Median overall survival and 5-year overall survival rate:
- Overall population: 46.6 months vs 48.8 months, and 42% vs 44% (HR = 1.01; P = .8834)
- Homologous recombination–deficient: 71.9 months vs 69.8 months, and 55% vs 56% (HR = 0.95; 95% CI = 0.70–1.29)
- Homologous recombination–proficient: 36.6 months vs 32.2 months, and 29% vs 27% (HR = 0.93; 95% CI = 0.69–1.26).
Progression-free survival rate at 5 years:
- Overall population: 22% vs 12% (HR = 0.66; 95% CI = 0.55–0.78)
- Homologous recombination–deficient: 35% vs 16% (HR = 0.51; 95% CI = 0.40–0.66)
- Homologous recombination–proficient: 8% vs 7% (HR = 0.67; 95% CI = 0.50–0.89).
Time to next treatment:
- Overall population: 17.0 months vs 12.0 months (HR = 0.74; 95% CI = 0.62–0.89)
- Homologous recombination–deficient: 26.9 months vs 13.9 months (HR = 0.55; 95% CI = 0.43–0.71)
- Homologous recombination–proficient: 11.6 months vs 7.9 months (HR = 0.88; 95% CI = 0.65–1.18).
The overall survival results for all prespecified biomarker-defined subgroups were consistent with the overall population. There were no differences between the arms in terms of a second progression-free survival.
The investigators proposed that the lack of overall survival benefit may not reflect niraparib’s efficacy but rather the impact of complicating factors, such as the extended postprogression survival and the use of subsequent therapy. A higher percentage of patients in the placebo arm experienced disease progression on treatment, and those patients were three times as likely to be treated with PARP inhibitors. In the overall population, subsequent PARP inhibitors were prescribed to 37.8% of the placebo group, but only 11.7% of the niraparib group, and to 48.4% and 15.8%, respectively, of the homologous recombination–deficient subset. Overall survival analyses adjusted for second-line PARP inhibitor use suggest that subsequent treatments may have had an impact, Dr. González-Martín added.
“With up to 7 years of follow-up, no new safety signals were observed,” he said. The incidence of myelodysplastic syndrome and acute myeloid leukemia was 2.3% with niraparib and 1.6% with placebo.
EXPERT POINT OF VIEW
Philipp Harter, MD, PhD
The invited discussant of the PRIMA trial was Philipp Harter, MD, PhD, of the Evang Kliniken Essen-Mitte in Essen, Germany. He shared these initial comments: “PRIMA met its primary endpoint, and the progression-free survival results were confirmed by this long-term follow-up…. Niraparib remains a standard option as maintenance therapy in patients with advanced ovarian cancer.”
The confirmation of benefit is “good news,” as is the observation that PARP inhibitors are safe in patients with primary ovarian cancer, Dr. Harter added. The incidence of myelodysplastic syndrome and acute myeloid leukemia is “something between 0% and 2%,” he said, far lower than rates seen with maintenance in relapsed disease.
While awaiting PRIMA’s overall survival analysis, other important trials have reported their results, and they are contradictory. “We’ve seen impressive overall survival data in BRCA-positive patients in SOLO1 (hazard ratio [HR] = 0.55; P = .0004)3 and “very promising data” for overall survival in BRCA-positive and homologous recombination–deficient patients in PAOLA-1 (HR = 0.62; 95% CI = 0.45–0.85).4 Both trials evaluated olaparib; PAOLA paired it with bevacizumab.
Dr. Harter had anticipated that PRIMA would also show an overall survival benefit or at least a favorable trend. “The only question for me was whether we would see a positive outcome in all subtypes,” he said. “But what we saw was no benefit, and this is disappointing.”
Reasons for Negative Outcomes Under Debate
Reasons for these results are being debated. It is unlikely to be “the drug itself,” because the Kaplan-Meier progression-free survival curves of the various trials are remarkably similar, noted Dr. Harter. Differences in the patient populations (especially ethnicity and risk profile) cannot be completely ruled out, although this is also unlikely, he suggested. Subsequent use of PARP inhibitors is similar enough among the trials that this is also an unlikely explanation.
The difference may be related to the duration of maintenance therapy, as differences have been shown in long-term outcomes for patients who relapse during or after PARP inhibitor maintenance, Dr. Harter pointed out. “We have good data that PARP inhibitor maintenance therapy also has some risks,” he said. “We should limit the duration of PARP inhibitor maintenance to 2 years or so, and maybe even 6 or 12 months. This is a very important question on which future trials should focus.”
DISCLOSURE: Dr. González-Martín has received fees from AbbVie, Alkermes, Amgen, AstraZeneca, BioNTech, Clovis Oncology, Daiichi Sankyo, Eisai, Genmab, GSK, Hedera Dx, ImmunoGen, Incyte, Illumina, Karyopharm Therapeutics, MacroGenics, Mersana Therapeutics, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Regeneron, Roche, Seagen, Sotio, Sutro Biopharma, Takeda, TORL, and Tubulis. Dr. Harter reported financial relationships with Amgen, AstraZeneca, GSK, Roche, Immunogen, Sotio, Stryker, Zai Lab, MSD, Clovis, Miltenyi, Eisai, Mersana, Exscientia, Daiichi Sankyo, Karyopharm, AbbVie, Corcept, and Bion Tech.
REFERENCES
1. González-Martín A, Pothuri B, Barretina-Ginesta MP, et al: Final overall survival in patients with newly diagnosed advanced ovarian cancer treated with niraparib first-line maintenance: Results from PRIMA/ENGOT-OV26/GOG-3012. ESMO Congress 2024. Abstract LBA29. Presented September 14, 2024.
2. González-Martín A, Pothuri B, Vergote I, et al: Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 381:2391-2402, 2019.
3. DiSilvestro P, Banerjee S, Colombo N, et al: Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: The SOLO1/GOG 3004 trial. J Clin Oncol 41:609-617, 2023.
4. Ray-Coquard I, Leary A, Pignata S, et al: Olaparib plus bevacizumab first-line maintenance in ovarian cancer: Final overall survival results from the PAOLA-1/ENGOT-ov25 trial. Ann Oncol 34:681-692, 2023.
