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Background: In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status. Patients and methods: Patients were randomized 2: 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis. Results: After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms. Conclusions: Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure. in press

Introduction/Background* The Phase III PAOLA-1/ENGOT-ov25 study (NCT02477644) demonstrated that the addition of olaparib to bevacizumab maintenance following standard platinum-based therapy plus bevacizumab improved progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer (Ray-Coquard et al. NEJM 2019). We aimed to describe safety, quality of life (QoL), and efficacy with olaparib plus bevacizumab in patients ≥70 years old. Methodology Safety (adverse events [AEs] graded according to CTCAE v5.0) and QoL (measured using EORTC QLQ-C30 global health status [GHS]) data were collected. We compared safety by age (older [≥70 years] and younger patients [ Result(s)* Of 806 patients enrolled, 142 (17.6%) were ≥70 years old; 104 of these were in the olaparib arm. There was no notable difference in baseline characteristics between olaparib and placebo arms (table 1). In evaluation of safety, moderately increased rates of grade ≥3 treatment-related AEs (TRAEs), dose reductions and interruptions, and treatment discontinuation due to TRAEs were reported in older than younger patients (table 2). Grade 3–4 any-cause anaemia (21.2% vs 16.5%) and neutropenia (9.7% vs 5.1%) were more frequent in older patients. The most common grade 3–4 non-haematological AE was hypertension (26.9% vs 16.7%). No acute myeloid leukaemia, myelodysplastic syndrome, or treatment-related death was reported among older patients. Interestingly, GHS during the first 2 years of maintenance was similar between arms. Median PFS was 21.1 months with olaparib vs 14.3 months with placebo. Analyses by GVS and homologous recombination deficiency subgroups are ongoing and will be presented. Conclusion* Among older patients in PAOLA-1, olaparib plus bevacizumab maintenance had a manageable safety profile and had no adverse impact on GHS. Median PFS in older patients was similar to the overall population. Analyses stratified by GVS will provide further insight into the safety profile of maintenance olaparib plus bevacizumab in older patients.

Background PM01183 is a new compound that blocks active transcription, produces DNA breaks and apoptosis, and affects the inflammatory microenvironment. PM01183 showed strong antitumor activity in preclinical models of cisplatin-resistant epithelial ovarian cancer. Patients and methods Patients with platinum-resistant/refractory ovarian cancer were included in a two-stage, controlled, randomized (in a second stage), multicenter, phase II study. Primary endpoint was overall response rate (ORR) by RECIST and/or GCIG criteria. The exploratory first stage (n = 22) confirmed the activity of PM01183 as a single agent at 7.0 mg flat dose every 3 weeks (q3wk). The second stage (n = 59) was randomized and controlled with topotecan on days 1–5 q3wk or weekly (every 4 weeks, q4wk). Results ORR was 23% (95% CI, 13%–37%) for 52 PM01183-treated patients. Median duration of response was 4.6 months (95% CI, 2.5–6.9 months), and 23% (95% CI, 0%–51%) of responses lasted 6 months or more. Ten of the 12 confirmed responses were reported for 33 patients with platinum-resistant disease [ORR = 30% (95% CI, 16%–49%)]; for the 29 patients treated with topotecan in the second stage, no responses were found. Median PFS for all PM01183-treated patients was 4.0 months (95% CI, 2.7–5.6 months), and 5.0 months (95% CI, 2.7–6.9 months) for patients with platinum-resistant disease. Grade 3/4 neutropenia in 85% of patients; febrile neutropenia in 21% and fatigue (grade 3 in 35%) were the principal safety findings for PM01183. Conclusion PM01183 is an active drug in platinum-resistant/refractory ovarian cancer and warrants further development. The highest activity was observed in platinum-resistant disease. Its safety profile indicates the dose should be adjusted to body surface area (mg/m2). Trial code EudraCT 2011-002172-16.

Introduction/Background In the Phase III SOLO1 first-line trial, maintenance therapy with the PARP inhibitor olaparib provided a substantial progression-free survival (PFS) benefit to advanced ovarian cancer (OC) patients who have a BRCA1/2 mutation (BRCAm) and are in complete or partial response to first-line chemotherapy (Moore K et al. N Engl J Med 2018). VEGF inhibitor may increase PARP sensitivity, particularly in some OC patients with BRCA wild type (Liu JF et al. Lancet Oncol 2014). PAOLA-1/ENGOT-ov25 (NCT02477644) is the first Phase III trial to evaluate the efficacy and safety of a PARP inhibitor with bevacizumab as first-line maintenance therapy, and in patients regardless of BRCAm status. Methodology PAOLA-1 is a randomized, double-blind, international Phase III trial. Eligible patients had newly diagnosed, advanced (FIGO stage IIIA-IV) high-grade serous or endometrioid ovarian, fallopian tube or peritoneal cancer. Patients had no evidence of disease or were in partial response following first-line platinum-based chemotherapy plus bevacizumab. Bevacizumab was to be given for up to 15 months, including the initial combination with chemotherapy. 806 patients were randomized (2:1) in maintenance therapy to olaparib (300 mg bid) or placebo plus bevacizumab (15 mg/kg, d1, q3w), stratified by first-line treatment outcome and tumour BRCAm status. The primary endpoint is investigator-assessed PFS (modified RECIST v1.1). The 458 PFS events required for the primary analysis to show significance at the two-sided 5% level with an estimated >80% power have been reached in March 2019. Database lock was in July and analyses are ongoing. Results The LBA will report: investigator-assessed PFS, PFS by BRCAm/HRD status, health- related quality of life, and safety and tolerability results. Conclusion PAOLA-1 will demonstrate whether addition of olaparib to bevacizumab maintenance therapy following first-line platinum-based chemotherapy plus bevacizumab provides a clinically meaningful benefit to OC patients. Disclosure P Harter declares honoraria from AstraZeneca, Roche, Sotio, Tesaro, Stryker, ASCO, Zai Lab and MSD; and consultancy/advisory board fees from AstraZeneca, Roche, Tesaro, Lilly, Clovis, Immunogen and MSD/Merck. Marie Ange Mouret-Reynier declares no conflicts of interest. S Pignata declares honoraria from Roche, AstraZeneca, MSD, Pfizer, Incyte, Novartis, PharmaMar, Clovis and Tesaro; and travel expenses from Roche, AstraZeneca and MSD. Claire Cropet declares no conflicts of interest. A Gonzalez-Martin declares consulting/advisory board fees from Roche, AstraZeneca, Tesaro, Clovis, Pfizer, ImmunoGen, PharmaMar, MSD, Genmad and Novartis; and speaker bureau/expert testimony fees from Roche, AstraZeneca, MSD Tesaro and PharmaMar. Gerhard Bogner declares consulting/advisory board fees from AstraZeneca Tesaro and Roche; and travel expenses from GSK, Roche, Pharmamar, AstraZeneca and Tesaro. K Fujiwara declares honoraria from AstraZeneca, Chugai Roche, Zeria, Taiho, Nihon Kayaku, Kyowahakko Kirin, Janssen and Daiichi Sankyo; consulting/advisory board fees from Pfizer, MSD and Eisai; research funding from AstraZeneca, MSD, Chugai Roche, Eisai and Kaken; and travel expenses from Pfizer. I Vergote declares consulting/advisory board fees from Advaxis, BIOCAD, Eisai, MSD, Roche, Genmab, Roche, PharmaMar, Millenium Pharmaceuticals, Clovis, AstraZeneca, Tesaro, Oncoinvent, ImmunoGen and Sotio; contracted research with Oncoinvent and Genmab; research funding from Amgen, Roche and Stichting tegen Kanker; and Takeda Oncology, PharmaMar, Genmab, Roche, AstraZeneca, Tesaro, Clovis and Immunogen. N Colombo declares honoraria from Roche, AstraZeneca, PharmaMar, Tesaro, Clovis, Pfizer, MSD, BIOCAD and Takeda; consulting/advisory board fees from Roche, AstraZeneca, PharmaMar, Tesaro, Clovis, Pfizer, MSD, BIOCAD, Takeda; and travel expenses from PharmaMar, Tesaro and Roche. J Maenpaa declares honoraria from Roche, AstraZeneca and Tesaro; consultancy/advisory board fees from AstraZeneca, Tesaro, Clovis and MSD; and travel expenses from Roche. Anne Floquet declares consultancy/advisory board fees from GSK, AstraZeneca and Clovis; and travel expenses from Roche, GSK and AstraZeneca. Ahmed El-Balat declares honoraria from AstraZeneca, Roche, Pharmamar, MSD, Tesaro, Clovis; and consultancy/advisory board fees from AstraZeneca and Roche. D Lorusso declares honoraria from Merck; consultancy/advisory board fees from Merck, AstraZeneca, Tesaro, Clovis, Immunogen, PharmaMar and Roche; research funding from Clovis, PharmaMar, Merck and Roche; and travel expenses from Tesaro, Roche and PharmaMar. EM Guerra Alia declares consultancy/advisory board fees from Roche, Clovis and AstraZeneca; and travel expenses from Roche and Baxter. Michel Fabro declares honoraria from Tesaro and AstraZeneca; and consultancy/advisory board fees from Tesaro and AstraZeneca. Barbara Schmalfeldt declares honoraria from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MSD; consultancy/advisory fees from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS; speaker bureau/expert testimony fees from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS; research grant funding from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS and travel expenses from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS. Anne Claire Hardy Blessard declares honoraria from AstraZeneca, Lilly, Novartis, Pfizer, Roche and Tesaro. Ingo Runnebaum declares honoraria from AstraZeneca. I Ray-Coquard declares honoraria from AstraZeneca, Clovis, Tesaro and PharmaMar; consulting/advisory board fees from AstraZeneca, Roche, Clovis, Tesaro, Genmab, PharmaMar, MSD and Pfizer; research funding from MSD; and travel expenses from AstraZeneca and Roche; consulting/advisory board fees from Roche; and travel expenses from Roche, MSD, Tesaro and AstraZeneca. E Pujade-Lauraine declares honoraria from AstraZeneca and Tesaro; consulting/advisory board fees from AstraZeneca, Roche, Clovis, Tesaro, Genmab, Incyte, MSD and Pfizer; research funding from AstraZeneca, Roche and Tesaro; and travel expenses from AstraZeneca, Roche and Tesaro.