Maintenance olaparib rechallenge improves PFS in ovarian cancer patients

Restarting treatment with maintenance olaparib in ovarian cancer patients who had received one prior poly(ADP-ribose) polymerase (PARP) inhibitor and at least two lines of platinum-based chemotherapy results in a modest but significant improvement in progression-free survival (PFS) compared with placebo, results of a phase III study have shown.

This survival benefit extends to both the BRCA-mutated and non-BRCA-mutated cohorts, with a fraction of patients in the maintenance olaparib rechallenge arm of both cohorts being progression free at 1 year.

“Statistically significant PFS benefit is seen with olaparib rechallenge over placebo independent of BRCA mutation status,” the investigators said. “No new safety signals were observed.”

Patients with platinum-sensitive relapsed ovarian cancer previously treated with PARP inhibitor for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy were included in this randomized, double-blind, multicentre trial.

The investigators then randomly assigned patients 2:1 to maintenance olaparib tablets 300 mg twice daily or placebo, with PFS as the primary endpoint. Specifically, 74 patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo.

In both cohorts, >85 percent of patients had been treated with at least three prior lines of chemotherapy. [Ann Oncol 2023;34:1152-1164]

The median PFS in the BRCA-mutated cohort was 4.3 months with olaparib relative to just 2.8 months with placebo (hazard ratio [HR], 0.57, 95 percent confidence interval [CI], 0.37‒0.87; p=0.022). PFS rates at 1 year were 19 percent with olaparib versus 0 percent with placebo based on Kaplan-Meier estimates.

In the non-BRCA-mutated cohort, the median PFS was 5.3 months with olaparib compared with 2.8 months with placebo (HR, 0.43, 95 percent CI, 0.26‒0.71; p=0.0023). Based on Kaplan-Meier estimates, 1-year PFS rates were 14 percent versus 0 percent.

“The initial rapid drop in the Kaplan–Meier PFS curves seen in both treatment arms and both cohorts … was not unexpected given that the population was heavily pretreated,” the investigators said.

“Patients typically continue PARP inhibitor maintenance therapy until disease progression in the relapsed disease setting and, given that most … patients had received prior PARP inhibitor maintenance therapy for relapsed disease, it is probable that some of these patients experienced disease progression because they developed PARP inhibitor resistance,” they added.

The present study did not explore the reasons for discontinuation of previous PARP inhibitor therapy.

On the other hand, patients treated with first-line maintenance PARP inhibitor therapy for a fixed duration were expected to face disease progression after finishing their maintenance therapy. They also had a lower likelihood of developing PARP inhibitor resistance, which could potentially improve the outcomes of rechallenge, according to the investigators.

Of note, no new safety signals were seen with olaparib rechallenge. Most adverse events (AEs) were mild (grade 1‒2) and usually manageable with dose modification. In addition, <3 percent of patients discontinued maintenance olaparib rechallenge due to AEs.

“Further investigation may reveal identifiable characteristics of those patients deriving the most clinical benefit,” the investigators said.