Despite sound rationale that patients with platinum sensitive non-small cell lung cancer (NSCLC) should also be sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), olaparib maintenance did not improve survival in a small under-enrolled phase II study. These findings were presented at the European Lung Cancer Virtual Congress 2021 (25-27 March).
Sophie Postel-Vinay of the Drug Development Department, Institut Gustave Roussy in Villejuif, France explained that DNA damage response (DDR) defects occur in NSCLC and that the DDR defects leading to platinum sensitivity widely overlap with those underlying sensitivity to PARP inhibitors, such as olaparib. Therefore, Dr. Postel-Vinay and co-investigators evaluated whether olaparib could be an effective maintenance treatment in patients with platinum-sensitive advanced NSCLC.
Olaparib as maintenance treatment was assessed in the randomised double-blind phase II PIPSeN (NCT02679963) study, which enrolled 180 chemonaïve patients with ECOG performance status (PS) 0-1, stage IIIB-IV NSCLC. The patients had no EGFR or ALK/ROS alterations.
After 4 to 6 cycles of platinum-based chemotherapy 60 patients achieving partial or complete response were randomly assigned to olaparib maintenance at 300 mg twice daily or placebo. Randomisation was stratified according to age, histology, and country.
The primary study objective was progression-free survival (PFS) from randomisation per RECIST v1.1. and secondary objectives included overall survival (OS) and safety.
The PIPSeN study was halted prematurely
PIPSeN required enrollment of 500 patients for randomisation of 144 patients to reach the anticipated hazard ratio (HR) of 0.65. However, due to the registration of anti-PD-L1 agents in the first-line setting, the study was closed prematurely.
Following randomisation, 33 patients were treated with olaparib maintenance and 27 received placebo. Their median age was 64 years, 64% had adenocarcinoma, and 3% of patients were never-smokers. Patient and tumour characteristics were well-balanced between arms, with the exception that 14 versus 8 patients had bone metastases and 11 versus 4 patients had peripheral lymphadenopathy in the olaparib and placebo arms, respectively.
Survival was not improved with olaparib as maintenance therapy
Median PFS was similar between arms at 2.3 months with olaparib maintenance versus 2.1 months with placebo (HR 0.89, 95% confidence interval [CI] 0.51-1.55; p = 0.68), as was median OS of 9.5 versus 14.1 months in the respective arms (HR 1.29; 95% CI 0.68-2.45; p = 0.44).
Subsequent systemic therapy was administered to 38 patients overall; of these, 23 were on olaparib and 15 were on placebo. Subsequent therapy included anti-PD(L)1 immune checkpoint blockers in 19 and 11 patients, and other immunotherapies in one and two patients of these respective arms.
Grade ≥3 adverse events (AEs) occurred in 20 patients receiving olaparib compared to 8 on placebo. Of 10 AEs leading to treatment discontinuation or treatment interruption, eight occurred in the olaparib arm.
Conclusions
The investigators noted that the PIPSeN study was terminated early due to being statistically underpowered, with only 50% of the pre-planned patient population available for analysis.
Although olaparib maintenance was well tolerated, neither median PFS nor median OS was improved by olaparib in this sample of patients with platinum-sensitive NSCLC.
This study was funded by AstraZeneca.
Reference
100MO - Postel-Vinay S, Planchard D, Antigny M, et al. Olaparib maintenance vs placebo in platinum-sensitive non-small cell lung cancer: The phase II randomized PIPSeN trial. European Lung Cancer Virtual Congress 2021 (25-27 March).