Maintenance Olaparib Retreatment Benefits Previously Treated Ovarian Cancer

OReO/ENGOT-ov38 [NCT03106987] is the first randomized placebo-controlled trial to report data for rechallenge with a PARP [inhibitor] in patients with [platinum-sensitive relapsed ovarian cancer," according to the study authors.

Maintenance olaparib (Lynparza) rechallenge resulted in a modest but statistically significant progression-free survival (PFS) benefit in a population of patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor and a minimum of 2 lines of platinum-based chemotherapy, according to data from the phase 3b OReO/ENGOT-ov38 study (NCT03106987).

Investigators reported a median PFS of 4.3 months in the olaparib arm compared with 2.8 months in the placebo cohort among patients with a BRCA mutation (HR, 0.57; 95% CI, 0.37-0.87; P = .022). Additionally, the 1-year PFS rates in this population were 19% vs 0%, respectively. A total of 103 PFS events took place in the BRCA-mutant population at data cutoff, translating to a data maturity of 92%.

Among those without a BRCA mutation, the median PFS was 5.3 months in the olaparib cohort vs 2.8 months in the placebo cohort (HR, 0.43; 95% CI, 0.26-0.71; P = .0023). The 1-year PFS rates were 14% vs 0%, respectively. Additionally, 78 PFS events took place in the non-mutant population, translating to a data maturity of 72%.

In the homologous recombination deficient (HRD)–positive, non-mutant population, the median PFS was 5.3 months in the olaparib cohort vs 2.8 months in the placebo cohort (HR, 0.52; 95% CI, 0.26-1.10), as well as 5.4 months vs 2.8 months in the HRD-negative, non-mutant group, respectively (HR, 0.49; 95% CI, 0.21-1.23).

“OReO/ENGOT-ov38 is the first randomized placebo-controlled trial to report data for rechallenge with a PARP [inhibitor] in patients with [platinum-sensitive relapsed ovarian cancer],” the authors wrote.

“In meeting its primary end point, OreO demonstrated that rechallenge with maintenance olaparib provided a statistically significant, albeit modest, improvement in PFS compared with placebo in both the BRCA [mutant] and non-BRCA [mutant] cohorts. PARP [inhibitor] maintenance therapy has typically provided a greater benefit in patients with BRCA [mutant] versus non-BRCA [mutant] tumors in the PARP [inhibitor]–naive [platinum-sensitive relapsed ovarian cancer] setting; however, in the OReO post-PARP [inhibitor] population, a similar beneficial effect was observed across the biomarker populations.”

The randomized, double-blind, placebo controlled, multicenter trial included patients with relapsed, histologically diagnosed, non-mucinous epithelial ovarian, primary peritoneal, and/or fallopian tube cancer. To be included in the study, patients needed to have serous, endometrioid, or transitional cell tumors or mixed histology if one of the aforementioned subtypes was predominant.

There was not a limit on prior lines of chemotherapy, although the most recent line of chemotherapy needed to consist of a minimum of 4 cycles of platinum-based chemotherapy; bevacizumab (Avastin) could not be used as part of this regimen. Those who enrolled on the study needed to be in complete or partial response to their most recent treatment with platinum-based chemotherapy. Patients with no evidence of disease after cytoreductive surgery with no sign of rising serum CA-125 levels were able to enroll on the study following an amendment to eligibility criteria.

Patients underwent random assignment within 8 weeks of the last dose of platinum-based chemotherapy, with stratification based on bevacizumab use prior to the most recent line of chemotherapy and number of previous lines of chemotherapy. The study used a 2:1 randomization, with patients receiving either 300 mg of olaparib twice daily or placebo; patients unable to receive the 300 mg dose of olaparib were able to receive 250 mg twice daily. Treatment lasted until radiological disease progression.

The study’s primary end point was PFS, with key secondary end points including time from randomization to first subsequent therapy or death, time from randomization to second subsequent therapy or death, overall survival (OS), health-related quality of life, and safety and tolerability.

The study included a total of 112 patients in the BRCA-mutant cohort who were randomly assigned from October 3, 2017 to April 15, 2020, as well as 108 patients in the non-BRCA–mutant cohort from June 28, 2017 to February 10, 2021.

The study population was heavily pretreated, with investigators reporting that more than 85% of patients had been previously treated with 3 or more lines of chemotherapy. Additionally, 7% and 14% of patients in the mutant and non-mutant cohorts, respectively, had a first relapse after undergoing treatment with maintenance PARP inhibitor in the first line.

The median duration of follow-up was 4.1 months (IQR, 2.7-8.5) in the olaparib cohort compared with 2.8 months (IQR, 2.7-5.5) in the placebo cohort for those with a BRCA mutation, as well as 2.9 months (IQR, 2.6-5.5) vs 2.8 months (IQR, 2.6-2.9) in the non-mutant population. The BRCA-mutant population had reached 50% data maturity for OS at the time of data cut-off.

Most adverse effects (AEs) were low-grade, with fatigue, nausea, and anemia being the most common in those retreated with maintenance olaparib.

Reference

Pujade-Lauraine E, Selle F, Scambia G, et al. Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial. Ann Oncol. 2023;34(12):1152-1164. doi:10.1016/j.annonc.2023.09.3110