The PARP inhibitor olaparib did not improve PFS or OS compared with placebo when used as a maintenance therapy for patients with platinum-sensitive NSCLC, according to results of the phase II PIPSeN trial.1
Sophie Postel-Vinay, MD, PhD, of the Gustave Roussy Cancer Campus in France, presented results of the trial at the European Lung Cancer Virtual Congress 2021.
Due to changes in the first-line standard-of-care treatment for NSCLC and the advent of immune checkpoint inhibitors, the trial was stopped early. With only 50% of the pre-planned patient population available for analysis, the trial was statistically underpowered.
DNA repair defects are very frequent in NSCLC and, notably, ERCC1 is a DNA repair enzyme that is defective in about 20% of NSCLC, Dr. Postel-Vinay said.
ERCC1 defects were correlated with platinum sensitivity in a clinical trial and with PARP inhibitor sensitivity in preclinical models of NSCLC. Therefore, the PIPSeN trial was designed to determine whether patients with platinum-sensitive NSCLC would benefit from PARP inhibition as a maintenance treatment, Dr. Postel-Vinay said.
The study included 60 patients with stage IIIB-IV NSCLC and no EGFR or ALK/ROS alterations who had not previously received chemotherapy. Patients whose disease had partially or completely responded after four to six cycles of platinum-based chemotherapy were randomly assigned to maintenance with 300 mg of olaparib twice a day or to placebo.
The primary endpoint was PFS from the time of assignment to a cohort. The researchers calculated that, to reach the primary endpoint, they would have needed to enroll 500 patients and to have randomly assigned 114 patients to each treatment arm. Secondary endpoints were OS and safety.
The median age of patients was 62 in the olaparib group and 65 in the placebo group. The majority of patients were male. All other characteristics were well balanced except for alcohol abuse, bone metastasis, and supraclavicular lymphadenopathy, which were more frequent in the olaparib arm.
No difference in PFS was detected between the group that received maintenance with olaparib and the one that received placebo. The median PFS was 2.3 months for the olaparib group compared with 2.1 months for the placebo group (hazard ratio [HR]=0.89; 95% CI, 0.51-1.55; p=0.68). Similarly, there was no significant difference in OS between the study arms. The median OS was 9.5 months for those receiving olaparib compared with 14.1 months for patients receiving placebo (HR = 1.29; 95% CI, 0.68-2.45; p = 0.44).
No new safety signals were detected in this patient population, with the expected toxicities for olaparib being predominantly gastrointestinal and hematologic. Ten adverse events led to treatment discontinuation; eight occurred in the olaparib arm.
“Further translational research is now needed to identify potential biomarkers of sensitivity to PARP inhibitors in this patient population,” Dr. Postel-Vinay said.
Commenting on the study was invited discussant Joachim G. Aerts, MD, PhD, of Erasmus MC University, the Netherlands, who questioned whether these results signal the end of PARP inhibition in NSCLC. However, he said, too many questions remain to know for sure, including whether concurrent use of PARP inhibitors may be better than sequential use, whether any conclusions can be drawn based on the small sample size of this trial, why patients in this population did not respond as well to PARP inhibition as those with specific other tumor types, and what role PARP inhibition might play in boosting the effects of immunotherapy in NSCLC.
- 1. Postel-Vinay S, Planchard D, Antigny M, et al. Olaparib maintenance vs placebo in platinum-sensitive non-small cell lung cancer: the Phase 2 randomised PIPSeN trial. Presented at: European Lung Cancer Virtual Congress 2021; March 25-27, 2021; Virtual. Presentation 100MO.