M. Beiner

Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial

Abstract Purpose: To explore whether patients with BRCA1/2-mutated or homologous recombination deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial. Patients and Methods: Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. Programmed death-ligand 1 (PD-L1) status of tumor-infiltrating immune cells (IC) was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious BRCA1/2 alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay. HRD was defined as gLOH ≥ 16%, regardless of BRCA1/2 mutation status. Potential associations between progression-free survival (PFS) and genomic biomarkers were evaluated using standard correlation analyses and log-rank of Kaplan–Meier estimates. Results: Among biomarker-evaluable samples, 22% (234/1,050) harbored BRCA1/2 mutations and 46% (446/980) were HRD. Median TMB was low irrespective of BRCA1/2 or HRD. Only 3% (29/1,024) had TMB ≥10 mut/Mb, and 0.3% (3/1,022) were MSI-high. PFS was better in BRCA2-mutated versus BRCA2–non-mutated tumors and in HRD versus proficient tumors. PD-L1 positivity (≥1% expression on ICs) was associated with HRD but not BRCA1/2 mutations. PFS was not improved by adding atezolizumab in BRCA2-mutated or HRD tumors; there was a trend toward enhanced PFS with atezolizumab in BRCA1-mutated tumors. Conclusions: Most ovarian tumors have low TMB despite BRCA1/2 mutations or HRD. Neither BRCA1/2 mutation nor HRD predicted enhanced benefit from atezolizumab. This is the first randomized double-blind trial in ovarian cancer demonstrating that genomic instability triggered by BRCA1/2 mutation or HRD is not associated with improved sensitivity to immune checkpoint inhibitors. See related commentary by Al-Rawi et al., p. 1645

Rucaparib maintenance for newly diagnosed advanced ovarian cancer: interim overall survival, progression-free survival, and safety at 5 years of follow-up from the phase III ATHENA-MONO/GOG-3020/ENGOT-ov45 study

We report the long-term efficacy and safety from the multicenter, randomized, double-blind, placebo-controlled, phase III ATHENA-MONO/GOG-3020/ENGOT-ov45 (NCT03522246) study of first-line rucaparib maintenance for advanced ovarian cancer. Patients were randomized 4 : 1 to oral rucaparib + intravenous (i.v.) placebo or oral + i.v. placebo. Stratification factors were homologous recombination deficiency (HRD; BRCA mutation and loss of heterozygosity status) classification, residual disease post-chemotherapy, and surgical timing. The primary endpoint was investigator-assessed progression-free survival (invPFS) in HRD and intent-to-treat (ITT) populations. Overall survival (OS) and safety were secondary endpoints. Second event of progression (PFS2) and time to first subsequent treatment (TFST) were exploratory. Interim OS and final safety analyses data cut-off was 9 March 2023. Updated invPFS, PFS2, and TFST analyses data cut-off was 5 May 2025. Median invPFS follow-up was ∼59 months for both rucaparib (HRD, n = 185; ITT, n = 427) and placebo (HRD, n = 49; ITT, n = 111). invPFS was significantly longer with rucaparib versus placebo in the HRD [31.4 versus 12.0 months; hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.35-0.76] and ITT (20.2 versus 9.2 months; HR 0.53, 95% CI 0.42-0.69) populations. Interim OS was immature (OS maturity: ITT 35%) with the median (95% CI) OS not reached with rucaparib and 46.2 (34.6-not reached) months with placebo for the ITT population (HR 0.83, 95% CI 0.58-1.17). ITT TFST (median 23.6 versus 12.1 months) and PFS2 (35.1 versus 26.9 months) were longer with rucaparib versus placebo. Overall, 34.6% of patients receiving rucaparib completed the 24-month treatment cap versus 17.3% receiving placebo. As of 5 May 2025, 40.0% of patients on rucaparib were still on study and in long-term follow-up. Safety remained consistent with the primary analysis. Rucaparib monotherapy provides significant and durable long-term benefit as first-line maintenance for patients with advanced ovarian cancer with and without HRD.

A Study of Atezolizumab Versus Placebo in Combination With Paclitaxel, Carboplatin, and Bevacizumab in Participants With Newly-Diagnosed Stage III or Stage IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

This is a Phase III, global, double-blind, 2-arm randomized study designed to compare the efficacy and safety of atezolizumab + paclitaxel + carboplatin + bevacizumab versus placebo + paclitaxel + carboplatin + bevacizumab. Study participants will have Stage 3 or 4 ovarian cancer (OC), fallopian tube cancer (FTC), or primary peritoneal cancer (PPC) with macroscopic residual disease postoperatively (i.e., after primary tumor reductive surgery) or who will undergo neoadjuvant therapy followed by interval surgery.