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Objective: To determine the safety and efficacy of the oral progesterone antagonist onapristone extended release (onapristone-XR) in patients with recurrent progesterone receptor (PR)-positive adult-type granulosa cell tumor (aGCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC)., Methods: This single-institution phase II study included patients with PR-positive aGCT, LGSOC, or EEC who received ≥1 prior line of chemotherapy. Patients were enrolled from 5/2019-5/2020. PR status was evaluated via immunohistochemistry. Eligible patients had PR expression ≥1% on tissue collected within 3 years of enrollment. Patients received 50 mg of onapristone-XR twice daily until disease progression or treatment discontinuation. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints were response duration, clinical benefit rate (CBR), and safety., Results: Five patients with LGSOC and 1 with EEC enrolled, but both cohorts closed early due to slow accrual. Fourteen patients with aGCT enrolled and completed stage 1 accrual. No responses were observed. Four patients with LGSOC were evaluable, with median PFS of 4.4 months (range, 1.8-NE) and CBR of 50% (range, 6.8%-93.2%). All 14 patients with aGCT were evaluable, with median PFS of 2.8 months (range, 1.6-4.9), 6-month PFS rate of 21.4% (range, 5.2%-44.8%), 12-month PFS rate of 14.3% (range, 2.3%-36.6%), and a CBR of 35.7% (range, 12.8%-64.9%)., Conclusions: The study did not meet its primary endpoint. While onapristone-XR was well tolerated in all 3 arms, no objective responses were observed., Competing Interests: Declaration of competing interest Alexia Iasonos reports consulting fees from Mylan. Chrisann Kyi reports grant funding from Conquer Cancer Foundation; grant funding paid to the institution from Merus, Gritstone, and BMS; and consulting fees from Scenic Immunology B.V. and OncLive. Rachel N. Grisham reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. Carol Aghajanian reports clinical trial funding paid to the institution from AstraZeneca; consulting fees (advisory board) from Eisai/Merck, Roche/Genentech, Abbvie, AstraZeneca/Merck, and Repare Therapeutics; advisory board participation (no fee) for Blueprint Medicine; and leadership/fiduciary roles for the GOG Foundation Board of Directors (travel cost reimbursement) and NRG Oncology Board of Directors (unpaid). Claire F. Friedman reports ongoing institutional research support from Merck, BMS, AstraZeneca, Mersana, Hotspot Therapeutics, Immunocore, Marengo and Volastra; consulting fees from BMS, Seagen, Aadi Biosciences, and Eli Lilly; honoraria for lectures from Onclive; meeting/travel support by Puma Biotechnology; and participation on Data Safety Monitoring or Advisory Board of Merck, Genentech, and Marengo (all uncompensated). Roisin E. O'Cearbhaill reports personal fees from Tesaro/GSK, Regeneron, R-PHARM, Seattle Genetics, Fresenius Kabi, Gynecologic Oncology Foundation, Bayer, Curio, Miltenyi, 2seventybio and Immunogen, and other from Hitech Health, all outside the submitted work. She is a non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK), and DUO-O (AstraZeneca) studies and non-compensated advisor for Carina Biotech. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Gynecologic Oncology Foundation, Genentech, Kite Pharma, Tesaro/GSK, Ludwig Cancer Institute, TCR2 Therapeutics, Genmab/Seagen Therapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Merck, Sellas Therapeutics, Abbvie/StemCentrx, Regeneron, Lyell Immunopharma, Acrivon, and Atara Biotherapeutics. Britta Weigelt reports a research grant from REPARE Therapeutics paid to the institution and has an immediate family member who is employed by AstraZeneca, outside the submitted work. Vicky Makker reports unpaid consulting/advisory roles with the following: Duality, Novartis, Morphosys, AstraZeneca, Eisai, Clovis Oncology, Karyopharm Therapeutics, GlaxoSmithKline, Merck, ArQule, Cullinan, Faeth Therapeutics, Jazz, Immunocore, Iteos Therapeutics, Ideaya, Kartos Therapeutics, Lilly, Moreo, Prelude, Takeda, and Zymeworks; research funding from the following: Merck (Inst), Eisai (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), Bayer (Inst), Takeda (Inst), Duality (Inst), Zymeworks (Inst), Karyopharm Therapeutics (Inst), Faeth Therapeutics (Inst), Bristol-Myers Squibb (Inst), Lilly (Inst), and Cullinan (Inst); travel, accommodations, and expenses from the following: Eisai, Merck, AstraZeneca; and a relationship with IBM. Dennis S. Chi reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE. The other authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Background: The phase III PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported., Patients and Methods: Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan-Meier methodology. OS testing was hierarchical [overall population first, then the homologous recombination-deficient (HRd) population]. Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cut-off date, 8 April 2024)., Results: The median follow-up was 73.9 months. In the overall population, the OS hazard ratio was 1.01 [95% confidence interval (CI) 0.84-1.23; P = 0.8834] for niraparib (n = 487) versus placebo (n = 246). In the HRd (n = 373) and homologous recombination-proficient (n = 249) populations, the OS hazard ratios were 0.95 (95% CI 0.70-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed., Conclusions: In patients with newly diagnosed advanced ovarian cancer at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Mirvetuximab soravtansine may be a potentially effective therapeutic option for ovarian low-grade serous carcinoma (LGSC), but the prevalence of folate receptor alpha (FRα) overexpression in this tumor type is unknown. We sought to characterize FRα expression in LGSC and its association with clinical and molecular features., Methods: FRα immunohistochemistry was performed on a tissue microarray comprised of 89 LGSCs and 42 ovarian serous borderline tumors (SBTs). Clinical tumor-normal panel-based sequencing was performed on 78 LGSCs. Associations between FRα-high status and clinicopathologic characteristics and survival outcomes were examined., Results: Of 89 LGSCs, 36 (40%) were FRα-high (≥75% of viable tumor cells exhibiting moderate-to-strong membranous expression). Of 9 patients with LGSC and samples from different timepoints, 4 (44%) had discordant results, with conversion from FRα-negative to FRα-high in 3 (33%) cases. There was no association between FRα-high status with age, race, or progression-free/overall survival. A MAPK pathway genetic alteration, most commonly involving KRAS (n = 23), was present in 45 (58%) LGSCs. Those lacking MAPK pathway alterations were more likely to be FRα-high compared to MAPK-altered LGSCs (61% vs 20%, p < 0.001). In SBTs, FRα-high expression was associated with high-risk (micropapillary) histology and/or subsequent LGSC recurrence compared to conventional SBTs without malignant recurrence (53% vs 9%, p = 0.008)., Conclusions: Future studies of FRα-directed therapy in patients with LGSC are warranted. Discordant FRα status at recurrence suggests potential benefit for retesting. A biomarker-driven approach to direct treatment selection in LGSC is recommended. As high FRα expression is more common amongst tumors lacking MAPK pathway genetic alterations, FRα testing to determine eligibility for mirvetuximab soravtansine therapy is particularly recommended for this subgroup., Competing Interests: Declaration of competing interest Y.L. Liu reports research funding from AstraZeneca, GSK, and Repare Therapeutics, outside the submitted work. A. Iasonos reports consulting fees from Mylan. D.S. Chi reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE. C. Aghajanian reports grant support paid to the institution from Abbvie, Clovis, Genentech, and AstraZeneca; consulting fees from Eisai/Merck, Mersana Therapeutics, Roche/Genentech, Abbvie, AstraZeneca/Merck, and Repare Therapeutics; advisory board participation for Blueprint Medicine; and unpaid participation on the Board of Directors of the GOG Foundation and NRG Oncology. R.E. O'Cearbhaill reports personal fees from Tesaro/GSK, Regeneron, R-PHARM, Seattle Genetics, Fresenius Kabi, Gynecologic Oncology Foundation, Bayer, Curio, Miltenyi, 2seventybio and Immunogen, and other from Hitech Health, all outside the submitted work. She is a non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK), and DUO-O (AstraZeneca) studies and a non-compensated advisor for Carina Biotech. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Acrivon, Lyell Immunopharma, and Gynecologic Oncology Foundation. K. Long Roche reports travel support from Intuitive Surgical. R.N. Grisham reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER, outside the submitted work. M.H. Chui reports consulting fees from Verastem Oncology, outside the submitted work. The other authors have no conflicts of interest to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)