Re-VOLVE: Phase II clinical trial in women with ovarian cancer progressing post-PARP inhibitor with treatment adapted to real-time assessment of evolving genomic resistance.

Abstract

5561 Background: As the use of PARPi increases in high-grade serous ovarian cancer (HGSOC) resistance mechanisms ultimately arise. Emerging therapeutic strategies to overcome PARPi resistance is a pressing concern. Re-VOLVE study is a phase II in HGSOC women post-PARPi with treatment adapted to real-time assessment of evolving genomic resistance to guide treatment decision (NCT05065021). Methods: It enrolled patients (pts) with HGSOC progressing post-PARPi to receive induction phase (IP) 2-3 cycles of niraparib 200-300mg/bevacizumab 7.5mg/kg followed by personalized phase based on initial RECIST response and real-time assessment of evolving genomic resistance from baseline biopsy (whole genome RNA sequencing/WGTS) and ctDNA (12 gene panel). If progression/stable disease after IP pts were assigned to cohort A (niraparib/bevacizumab/dostarlimab 500mg) if no resistance mechanisms and to B (weekly paclitaxel 80mg/m2/bevacizumab/dostarlimab) if any present and to cohort C (continue niraparib/bevacizumab) if partial response after IP. Primary endpoint was to assess response rate of combination therapies. Results: 50 pts were screened; 7 were screen fail and 43 were enrolled. Of the 43, 3 pts were taken off due to progression during IP, 1 withdrew from study, 3 are on IP and 36 continued to personalized phase. Of these 36, 78% were white, 20% Asian, 2% others; 69% BRCA wild-type (25/36); 61% platinum-resistant (PR;22/36) and 39% platinum-sensitive (PS;14/36). Median age 62.5 years (33-87). Pts had median 2 prior therapy lines (1-5); 22% (8/36) prior bevacizumab. Median days from collection to ctDNA results were 59 days and to WGTS 54 days. Twenty-seven pts (75%) had biopsy and ctDNA to guide therapy. 36 pts were assigned to personalized phase: 78% cohort A, 14% to B (4 CCNE1 amplification and 1 CHEK2 mutation) and 8% to C (3 with response during IP). Of the 31/36 pts assessed for response during personalized phase (others too early) 10 achieved partial response (32.2%; 7 PR, 3 PS). Nineteen pts (61.3%; 11 PR, 8 PS) had stable disease. By cohort, 3 pts had partial response (12.5%; 3/24) cohort A, 4 partial response cohort B (100%; 4/4 all with resistance mechanisms) and 3 partial response (100%; 3/3) cohort C. Median PFS in the personalized phase was 7.8 months (m) for those in cohort A, 6.2m for B and 13.1m for C. Median PFS for PR pts was 6.9m (4.4-13.1) and for PS pts not reached. Grade (G) 3 AE related to therapy per cohort: A) 4 pts with anemia, 2 neutropenia, 1 thrombocytopenia, 1 nausea; B) 2 pts neutropenia; C) no G3. No G4 AE. No G3-G4 immune related AE. Conclusions: These findings highlight the potential clinical activity of a chemo-free approach and confirmed the feasibility of guiding personalized therapy in real-time in recurrent OC pts post-PARPi. This strategy was safe and provided clinical benefit to some pts. Further translational analysis is ongoing. Clinical trial information: NCT05065021 .