Phase 3 Clinical Trials Evaluating Poly(ADP-Ribose) Polymerase Inhibition Plus Immunotherapy for First-Line Treatment of Advanced Ovarian Cancer

Abstract Ovarian cancer is the second deadliest gynecologic malignancy globally. Current standard of care first-line therapy for newly diagnosed advanced epithelial ovarian cancer is surgery and platinum-based chemotherapy (±bevacizumab), followed by maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor, bevacizumab, or a combination of the two. Although anti–programmed cell death (PD) protein 1 and anti–PD ligand 1 antibodies (PD-L1 inhibitors) have shown benefit in several solid tumors, their effect in ovarian cancer remains uncertain. Several trials are evaluating PD-(L)1 inhibitors in combination with first-line platinum-based chemotherapy and PARP inhibitor maintenance treatment. Here, we review trial designs to understand key similarities and differences for future assessments of the results. The clinical trials registry “ClinicalTrials.gov” was searched using keywords, including ovarian cancer and niraparib, olaparib, or rucaparib. Search results were then filtered for phase 3 and manually reviewed to identify trials evaluating combinations of PARP inhibitors and PD-(L)1 inhibitors in the first-line setting. Four trials, ENGOT-OV44/FIRST (NCT03602859), ENGOT-OV46/AGO-OVAR 23/GOG-3025/DUO-O (NCT03737643), ENGOT-OV43/GOG-3036/KEYLYNK-001 (NCT03740165), and ENGOT-OV45/GOG-3020/ATHENA (NCT03522246), were identified. Of these, FIRST, DUO-O, and KEYLYNK-001 are evaluating both first-line use in combination with chemotherapy and maintenance, whereas ATHENA focuses on maintenance after a response to chemotherapy; however, DUO-O and KEYLYNK-001 do not include a PARP inhibitor in the comparator arm, limiting the ability to compare the added benefit of immunotherapy over the current standard of care. Results of these trials will determine whether PARP inhibitor and PD-(L)1 inhibitor combination with or without bevacizumab can improve patient outcomes.