Exploring the significance of PARP inhibitor therapy after first-line chemotherapy in patients with homologous recombination proficient ovarian cancer: An extracted individual patient data and trial-level meta-analysis.

Abstract

5580 Background: The use of poly (ADP-ribose) polymerase inhibitors (PARPi) as maintenance therapy in advanced epithelial ovarian cancer (EOC) patients (pts) has shown to delay cancer progression among patients with mutated BRCA (mBRCA) or homologous recombination deficiency (HRD), with debatable and divergent benefit among the subgroup of patients with homologous recombination proficiency (HRP). We aimed to further clarify the efficacy of PARPi after first-line chemotherapy (1L CT) in patients with HRP EOC. Methods: A systematic literature search of PubMed, Embase, The Cochrane Library until February 9th was conducted to identify articles or presentations of phase III clinical trials (P3CT) evaluating PARPi maintenance therapy after 1L CT in ovarian cancer. Individual patient data was reconstructed from Kaplan-Meier plots of progression-free survival (PFS) among pts with mBRCA, HRD and HRP through WebPlotDigitizer and R package IPDfromKM and futher combined. We also performed trial-level meta-analysis with a random effects model. Comparisons were made with Cox proportional hazards. Clinical benefit for each sub-group was accessed with the ESMO Magnitude of Clinical Benefit Formulary 2b (ESMO MBCS). Results: The literature search resulted in 513 items. After screening, 6 P3CT (SOLO1, PRIMA, VELIA, PAOLA, PRIME, and ATHENA-MONO) were selected, and the longer follow-up data of each trial was used. A total of 3205 pts were included in the analysis (2090 in PARPi arms, 1115 in control arms). HRP was associated with worse PFS regardless of the treatment arm (HRP vs mBRCA in PARPi arms: HR 1.92, 95% CI 1.62 – 2.21, P < 0.001). Compared to control treatment arm, PARPi therapy was associated with a improved PFS in all subgroups, although the magnitude of benefit decreased from mBRCA to HRD and HRP (Table). Trial-level meta-analysis yielded similar results. PARPi therapy summed 4 out of 4 possible points at ESMO MBCS for mBRCA and HRD, but only 2 points among HRP pts, confirming a lower clinical benefit in this subgroup. Conclusions: This meta-analysis included additional P3CT recently presented and new data of subgroup analysis of previous studies. Results confirm a statistically significant benefit of PARPi maintenance after 1L CT for HRP EOC. Nevertheless, the relative and absolute gain in PFS is modest (9% in 2 years), while mBRCA and HRD subgroups have a substantial benefit. The worse prognosis of HRP pts, in addition to the small clinical benefit of PARPi therapy, highlights the need for new treatment strategies for this subgroup. [Table: see text]