Characterization of patients with BRCA mutated ovarian cancer who are eligible versus not eligible for PARP inhibitor maintenance therapy: exploratory analysis of the VELIA study

Abstract

<h3>Objectives:</h3> Previous phase 3 trials of front-line maintenance with the PARP inhibitors (PARPi) olaparib and niraparib only included patients (pts) with complete (CR) or partial (PR) response following front-line chemotherapy (CT); both agents were adopted as standard of care (SOC) in these pts. This prevented the systematic study of all pts who are eligible for PARPi maintenance therapy after front-line CT or to predict their responses. The phase 3 VELIA study (NCT02470585) added veliparib (VEL) to front-line CT at diagnosis, followed by VEL maintenance in the absence of progressive disease (PD), permitting treatment of a broader cohort of pts. This exploratory analysis evaluated baseline characteristics associated with first-line CT response, to understand if predictive variables exist that could identify those who would be eligible vs ineligible for SOC PARPi maintenance. <h3>Methods:</h3> Pts with untreated Stage III/IV ovarian cancer were randomized to carboplatin/paclitaxel (CP) + placebo (PBO) followed by PBO maintenance (control arm), CP + VEL followed by PBO maintenance (VEL combination only), or CP + VEL followed by VEL maintenance (VEL throughout). Pts without progression after combination treatment transitioned to assigned maintenance therapy. In this exploratory analysis, pts with germline or somatic <i>BRCA</i> mutations (BRCAm) were grouped as maintenance eligible (ME; with CR/PR or non-PD with surgical complete resection) or maintenance not eligible (MNE; with stable disease/progression/non-CR/non-PD). Progression-free survival (PFS) in pts starting maintenance was measured from initiation of maintenance treatment. <h3>Results:</h3> Of 1,140 randomized pts, 298 had germline or somatic <i>BRCA</i>m; of these, 278 could be classified according to maintenance eligibility. MNE pts (n=56) were distributed equally among the control, VEL combination only, and VEL throughout arms (21%, 19%, and 21% of evaluable pts, respectively). MNE subgroups were enriched for advanced disease (18-39% of MNE subgroups vs 13-19% of ME subgroups had Stage IV disease) and less favorable performance status (41-67% MNE vs 20-40% of ME pts had ECOG performance status ≥1). For ME pts (n=222), median PFS from initiation of maintenance was not reached in the VEL throughout arm vs 19.7 months in the control arm (HR 0.29, 95% CI 0.16-0.52, Figure). For MNE pts, median PFS was 16.4 months in the VEL throughout arm and 18.9 months in the control arm (HR 1.331, 95% CI 0.52-3.44); however, sample sizes (n=18 and n=16, respectively) limit a meaningful analysis of PFS in these pts. <h3>Conclusions:</h3> The results of this exploratory analysis suggest that VEL has robust efficacy in pts with BRCA-mutated tumors eligible for SOC PARPi maintenance. Baseline characteristics of advanced disease and less favorable performance status were more common in MNE pts than ME pts. Molecular characterization is ongoing to identify mechanisms of sensitivity that predict eligibility for, and response to, PARPi therapy.