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Annals of Oncology : Official Journal... Aug 2023In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Humans; Female; Bevacizumab; Ovarian Neoplasms; Antineoplastic Agents; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Maintenance Chemotherapy
PubMed: 37211045
DOI: 10.1016/j.annonc.2023.05.005 -
Annual Review of Pathology Jan 2024Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been... (Review)
Review
Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been linked to malignant processes. Tremendous advancements over the past years have led to a deeper understanding of the role of somatic mutations in benign and malignant age-related diseases. Here, we review the somatic mutations that accumulate in the blood and their connection to disease states, with a particular focus on inflammatory diseases and myelodysplastic syndrome. We include a definition of clonal hematopoiesis (CH) and an overview of the origins and implications of these mutations. In addition, we emphasize somatic disorders with overlapping inflammation and hematologic disease beyond CH, including paroxysmal nocturnal hemoglobinuria and aplastic anemia, focusing on VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Finally, we provide a practical view of the implications of somatic mutations in clinical hematology, pathology, and beyond.
Topics: Humans; Clonal Hematopoiesis; Hematologic Neoplasms; Myelodysplastic Syndromes; Aging; Inflammation; Hematopoiesis
PubMed: 37832948
DOI: 10.1146/annurev-pathmechdis-051222-122724