乌鸦传媒

For women with platinum-sensitive recurrent ovarian cancer, maintenance therapy using an individualized starting dose of niraparib (Zejula) did not improve overall survival (OS) despite producing a statistically and clinically significant progression-free survival (PFS) benefit in the phase III NORA study.

An interim analysis of the key secondary endpoint showed a median OS of 46.3 months for patients receiving niraparib versus 43.4 months for patients receiving placebo (HR 0.82, 95% CI 0.56-1.20) in the trial's intent-to-treat (ITT) population, reported Mansoor Raza Mirza, MD, of Rigshospitalet, Copenhagen University Hospital in Denmark.

Even after adjusting for the 43% of controls who crossed over to receive a PARP inhibitor, investigators failed to show a significant increase in OS among niraparib users (46.3 months vs 34.3 months, HR 0.69, 95% CI 0.45-1.07), according to his presentation at a virtual plenary session.

The study's previously reported showed a median 18.3 months with the PARP inhibitor and 5.4 months with placebo (HR 0.32, 95% CI 0.23-0.45) among 265 Chinese patients.

Mirza maintained that niraparib produced a "favorable" survival trend irrespective of biomarker status compared with placebo.

In a predefined analysis, median OS in patients with a BRCA mutation was not reached for patients receiving niraparib compared with 47.6 months with the placebo group (HR 0.76, 95% CI 0.40-1.46). Median OS in the non-BRCA subgroup was 43.1 months versus 38.4 months, respectively (HR 0.86, 95% CI 0.53-1.38).

As for PFS, niraparib was associated with significant clinical benefit for both subgroups:

• BRCA: HR 0.22 (95% CI 0.12-0.39)
• Non-BRCA: HR 0.40 (95% CI 0.26-0.61)

One strength of Mirza's report was that it provided "important and necessary information due to recent concerns about OS in patients with non-BRCA mutated tumors treated with PARP inhibitor maintenance in relapse," commented Antonio González-Martin, MD, PhD, of Clinica Universidad de Navarra in Spain.

In fact, that, at the request of the FDA, it is restricting the second-line maintenance indication for niraparib to just patients with deleterious or suspected deleterious germline BRCA mutations. That decision followed an FDA review of the final OS analysis of the ENGOT-OV16/NOVA phase III trial, which served as the basis for the approval of the second-line maintenance indication. In the NOVA trial, the secondary endpoint of OS did not reach significance (HR 1.06, 95% CI 0.81-1.37) in the non-BRCA cohort.

González-Martin pointed out that the neutral effect on OS seen in NOVA for patients without a BRCA mutation was contradictory to the favorable trend demonstrated in NORA.

He suggested that with NORA's results, as well as results from other trials of PARP inhibitors in the maintenance setting, PARP inhibitors "should be used as maintenance therapy" after a response to platinum rechallenge in patients with BRCA-mutated tumors who were not previously exposed to PARP inhibitors. This, he said, is based on the positive effect on PFS from rucaparib (Rubraca) in ARIEL3, olaparib (Lynparza) in SOLO-2, and niraparib in NOVA and NORA; the positive effect on PFS-2 observed in SOLO-2, NOVA, and ARIEL3; as well as the positive trend seen in OS in all four studies.

As for patients with non-BRCA mutated tumors not previously exposed to PARP inhibitors, he said they "should be considered as maintenance therapy" after response to platinum rechallenge in patients, based on the positive effect on PFS observed in NORA, NOVA, and ARIEL3, supported by positive effects on PFS-2 in NOVA and ARIEL3, and the positive OS trend demonstrated in NORA.

"PFS, PFS-2, and time to second subsequent therapy are valid endpoints in recurrent ovarian cancer for making individual patient's clinical decisions, and support the use of PARP inhibitor maintenance in second or further lines," González-Martin said. "Patients with non-BRCA-mutated tumors [who are] candidates to receive PARP inhibitors as maintenance in the recurrent setting should be informed about contradictory data on OS and the limitations in their interpretation."

NORA included patients with platinum-sensitive, recurrent cancer with high-grade serous or high-grade predominantly serous histology. They also had to have completed at least two previous lines of platinum-containing therapy, and were in partial or complete remission after the last platinum-based chemotherapy. The OS data for the ITT analysis was at 44% maturity (median follow-up of 45.7 months for the niraparib arm and 44.5 months for the placebo arm).

Patients were randomized 2:1 to receive niraparib (n=177) or placebo (n=88) once daily until disease progression or unacceptable toxicity.

While no new safety signals were identified, Mirza noted that two patients in the niraparib arm developed myelodysplastic syndrome/acute myeloid leukemia.

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