A phase IIIb randomized, double-blind, placebo-controlled clinical trial has found that maintenance olaparib rechallenge provided a modest but statistically significant improvement in progression-free survival (PFS) compared to placebo in patients with platinum-sensitive relapsed ovarian cancer who had previously received poly(ADP-ribose) polymerase (PARP) inhibitor therapy. The OReO/ENGOT-ov38 study, funded by AstraZeneca and Merck Sharp & Dohme LLC, was published in Annals of Oncology on October 4, 2023.
The trial aimed to evaluate the efficacy and safety of PARP inhibitor rechallenge in patients with platinum-sensitive relapsed ovarian cancer who were in response to platinum-based chemotherapy and had previously received a PARP inhibitor. This multicenter study enrolled patients across multiple countries and randomized them 2:1 to receive either maintenance olaparib tablets 300 mg twice daily or placebo.
A total of 220 patients were included in the trial, divided into two cohorts based on BRCA mutation status. The BRCA-mutated cohort consisted of 112 patients (74 olaparib, 38 placebo), while the non-BRCA-mutated cohort had 108 patients (72 olaparib, 36 placebo). Eligible patients had histologically diagnosed non-mucinous epithelial ovarian cancer, primary peritoneal cancer, and/or fallopian tube cancer. They were required to have received one prior course of maintenance therapy with any PARP inhibitor in any prior line of therapy.
The inclusion criteria differed slightly between the two cohorts. In the BRCA-mutated cohort, patients needed to have received prior PARP inhibitor therapy for ≥18 months following first-line chemotherapy or ≥12 months following a second or subsequent line of chemotherapy. For the non-BRCA-mutated cohort, the requirements were ≥12 months following first-line chemotherapy or ≥6 months following a second or subsequent line of chemotherapy.
Baseline characteristics were generally balanced between treatment arms within each cohort. The median age ranged from 58.5 to 66.5 years across the groups. Notably, patients were heavily pretreated, with over 85% in both cohorts having received ≥3 prior lines of any chemotherapy. Only 7% of BRCA-mutated patients and 14% of non-BRCA-mutated patients were included at first relapse after having received a maintenance PARP inhibitor as part of first-line therapy.
The primary endpoint of the study was investigator-assessed PFS. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.37-0.87; P=0.022). The 1-year PFS rates were 19% versus 0% (Kaplan-Meier estimates). For the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P=0.0023), with 1-year PFS rates of 14% versus 0%.
Secondary endpoints included time to first subsequent therapy or death (TFST), time to second subsequent therapy or death (TSST), overall survival (OS), health-related quality of life (HRQoL), and safety. TFST was significantly improved with olaparib versus placebo in both cohorts. In the BRCA-mutated cohort, median TFST was 5.8 versus 5.1 months (HR 0.56; 95% CI 0.36-0.88; P=0.0117). For non-BRCA-mutated patients, median TFST was 7.9 versus 4.3 months (HR 0.39; 95% CI 0.23-0.65; P=0.0011).
OS analysis in the BRCA-mutated cohort, conducted at 54% data maturity, showed no significant difference between olaparib (median 20.1 months) and placebo (median 20.9 months) arms (HR 0.88; 95% CI 0.52-1.53; P=0.44). OS data were immature in the non-BRCA-mutated cohort, with only 21% of patients having died at the time of data cut-off.
The safety profile of maintenance olaparib rechallenge was consistent with previous studies, with no new safety signals identified. The most commonly reported adverse events in patients receiving olaparib were fatigue/asthenia, nausea, and anemia, with most adverse events being grade 1-2. Serious adverse events were reported in 7% of olaparib patients in the BRCA-mutated cohort and 15% in the non-BRCA-mutated cohort.
The study had several limitations. The OReO population had a poor prognosis, contributing to a shorter-than-planned median PFS. The slower recruitment to the non-BRCA-mutated cohort resulted in early censoring and a shorter duration of follow-up compared to the BRCA-mutated cohort. As the final data cut-off criteria were met, outcomes data with a longer duration of follow-up, including median OS in the non-BRCA-mutated cohort, will not be available.
Additionally, recruitment to OReO started before PARP inhibitors became available in the first-line setting, so very few patients received maintenance olaparib rechallenge as part of second-line therapy. The absence of information concerning reasons for discontinuation of prior PARP inhibitor therapy also represents a study limitation. The short duration of follow-up means that data on longer-term safety, including myelodysplastic syndrome and acute myeloid leukemia events, are limited.
The authors concluded that in ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts. A proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remained progression-free at 1 year.
The potential clinical impact of this study is significant, as it is the first randomized trial to demonstrate a benefit from PARP inhibitor rechallenge in patients with platinum-sensitive relapsed ovarian cancer who have previously received PARP inhibitor therapy. The results suggest that maintenance olaparib rechallenge could be a valuable treatment option for some patients, regardless of BRCA mutation status.
However, the modest improvement in median PFS (approximately 2 months) and the lack of overall survival benefit in the BRCA-mutated cohort indicate that careful patient selection may be necessary to identify those most likely to benefit from this approach. The study also raises questions about the development of PARP inhibitor resistance and its impact on subsequent therapies, highlighting the need for further research in this area.
In conclusion, the OReO/ENGOT-ov38 trial provides important evidence supporting the potential use of PARP inhibitor rechallenge in selected patients with platinum-sensitive relapsed ovarian cancer. While the benefits observed were modest, the study opens up new avenues for research and treatment strategies in this challenging patient population. Future studies may help to identify biomarkers or clinical characteristics that could predict which patients are most likely to benefit from PARP inhibitor rechallenge, potentially leading to more personalized treatment approaches in ovarian cancer management.
References
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
