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Background: There are no approved treatments specifically for low grade serous ovarian cancer; current standard of care treatment options are limited in efficacy and tolerability. The combination of avutometinib with defactinib has demonstrated efficacy and a consistent safety profile in two clinical trials in recurrent low grade serous ovarian cancer, and a lower discontinuation rate due to adverse events compared with historical rates for standard of care., Primary Objective: To compare the progression free survival of the combination of avutometinib with defactinib versus investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer., Study Hypothesis: Combination treatment with avutometinib-defactinib will significantly improve progression free survival compared with investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer., Trial Design: GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301 is a phase 3, randomized, international, open label study designed to compare avutometinib with defactinib versus investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer who have progressed on a previous platinum based therapy. On confirmation of disease progression using a blinded independent central review, patients on the investigator's choice of treatment arm may cross over to the avutometinib-defactinib arm., Major Inclusion/exclusion Criteria: Patients must have recurrent low grade serous ovarian cancer ( KRAS mutant or wild-type) and have documented progression (radiographic or clinical) or recurrence of low grade serous ovarian cancer after at least one platinum based chemotherapy regimen. Unlimited additional previous lines of therapy are allowed, including previous MEK/RAF inhibitor. Patients will be excluded if they have co-existing high grade ovarian cancer or had previous treatment with avutometinib, defactinib, or any other FAK inhibitor., Primary Endpoint: Progression free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded-independent central review., Sample Size: Approximately 270 patients will be randomized in a 1:1 fashion to either the combination avutometinib with defactinib arm (n~135) or the investigator's choice of treatment arm (n~135)., Estimated Dates for Completing Accrual and Presenting Results: The estimated primary completion date of RAMP 301 is 2028, and the estimated study completion date is 2031., Trial Registration: ClinicalTrials.gov NCT06072781., Competing Interests: Competing interests: YCL discloses institutional research grants from BeiGene and honoraria from AstraZeneca. CAA discloses institutional trial funding from Abbvie, Artios Pharma, AstraZeneca, Clovis, and Genentech/Roche. PT discloses advisory board participation with Iovance, AstraZeneca, Clovis, GSK, Seagen, Agenus, Relacorilant, Immunogen, Mersana, Novocurfe, Zentalis, Merck, and Caris. RLC discloses grants from AstraZeneca, Clovis, Genelux, Genmab, Merck, Immunogen, Roche/Genentech, Karyopharm, royalties from Up To Date, and consulting fees or honoraria from Agenus, Alkermes, AstraZeneca, Clovis, Deciphera, Genelux, Genmab, GSK, Immunogen, OncoQuest, Onxerna, Regeneron, Karyopharm, Roche/Genentech, Novocure, Merck, and Abbvie. BJM discloses consulting fees or honoraria from Acrivon, Adaptimmune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, CLovis, Eisai, Elevar, EMD Merck, Genmab, GOG Foundation, Gradalis, Heng Rui, Immunogen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, GSK, Sorrento, USO, VBL, Verastem, and Zentalis. DG discloses royalties from UpToDate and Elsevier, consulting fees from Verastem, honoraria from Johns Hopkins, and stock in BMS, J&J, Proctor, and Gamble. RG discloses consulting fees from GSK, AstraZeneca, Myriad, Natera, GOG Foundation, honoraria from PRIME, IDEOlogy, Curio, and funding support by the NIH/NCI cancer center support grant P30 CA 008748. KNM discloses institution research funding from PTC therapeutics, Lilly, Clovis, Genentech, GSK, Verastem, royalties from UpToDate, and consulting fees or honoraria from AstraZeneca, Aravive, Aadi, Blueprint, Clovis, Caris, Duality, Eisai, GSK, Genentech/Roche, Hengrui, Immunogen, Iovance, Janssen, Lilly, Mereo, Mersana, Merck, Myriad, Novartis, Novocure, Pannavance, Onconova, VBL, Verastem, Zentalia, PRIME, RTP, Medscape, Great Debates, and Updates. PH discloses grants or honoraria from AstraZeneca, Roche, GSK, Genmab, Immunogen, Seagen, Clovis, Novartis, Amgen, Mersana, Sotio, Stryker, Zai Lab, MSD, Clovis, Eisai, Daiichi Sankyo, and Karyopharm. MRM discloses consulting fees from GSK, AstraZeneca, Immunogen, Merck, Merck KGA, and stock and leadership position with Karyopharm. AO discloses consulting fees or honoraria from Agenus, AstraZeneca, Clovis, Corcept, Deciphera, Daiichi Sankyo, Debiopharm, Eisai, Exelixis, Roche, Genmab, GSK, Immunogen, Itheos, MSD, Mersana, Myriad, Novocure, OncoXerna, PharmaMar, Regeneron, Shattuck Labs, Seagen, Sutro, TORL, Zentalis, and Zymeworks. DMO discloses institutional research funds from Abbvie, Advaxis, Agenus, Alkermes, Aravive, Arcus, AstraZeneca, BeiGene, Boston Biomedical, BMS, Clovis, Deciphera, Eisai, EMD Serono, Exelixis, Genentech, Genmab, GSK, Roche, Immunogen, Incyte, Iovance, Karyopharm, Leap, Merck, Mersana, NCI, Novartis, Novocure, OncoC4, OncoQuest, Pfizer, Precision Therapeutics, Prelude, Regeneron, RTOG, Seagen, Sutro, and SWOG, consulting fees from Abbvie, Adaptimmune, Agneus, Arquer, Arcus, AstraZeneca, Atossa, Boston Biomedical, Cardiff Oncology, Celcuity, Clovis, Corcept, Duality Bio, Eisai, Elevar, Exelixis, Genetech, Genelux, GSK, Roche, Immunogen, Imvax, Intervenn, InxMed, Iovance, Janssen, Jazz, Laekna, Leap, Luzsana Biotechnology, Merck, Mersana Myriad, Novartis, Novocure, OncoC4, Onconova, Regeneron, RepImmune, RPharm, Roche, SeaGen, Sorrento, Sutro, Tarveda, Toray, Trillium, Umoja, Verastem, VBL, Vincerx Pharma, Xencor, and Zentalis. AMO discloses institutional funding from AstraZeneca, and Amgen. SB discloses consulting fees or honoraria from AstraZeneca, Epsilogen, GSK, Immunogen, ITM Oncologics, MSK, Mersana, Myriad, Novartis, Oncxerna, Seagen, Shattuck, Regeneron, Verastem, Abbvie, Pfizer, Takeda, and Novocure. EVN discloses consulting fees or honoraria from AstraZeneca, Oncoinvent, Regeneron, GSK, and Merck. NC discloses consulting fees or honoraria from Novocure, AstraZeneca, Clovis, Eisai, GSK, Immunogen, Mersana, MSD, Pfizer, Roche/Genentech, Pieris, and Novartis., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Motivation: Circulating-cell free DNA (cfDNA) is widely explored as a noninvasive biomarker for cancer screening and diagnosis. The ability to decode the cells of origin in cfDNA would provide biological insights into pathophysiological mechanisms, aiding in cancer characterization and directing clinical management and follow-up., Results: We developed a DNA methylation signature-based deconvolution algorithm, MetDecode, for cancer tissue origin identification. We built a reference atlas exploiting de novo and published whole-genome methylation sequencing data for colorectal, breast, ovarian, and cervical cancer, and blood-cell-derived entities. MetDecode models the contributors absent in the atlas with methylation patterns learnt on-the-fly from the input cfDNA methylation profiles. In addition, our model accounts for the coverage of each marker region to alleviate potential sources of noise. In-silico experiments showed a limit of detection down to 2.88% of tumor tissue contribution in cfDNA. MetDecode produced Pearson correlation coefficients above 0.95 and outperformed other methods in simulations (P < 0.001; T-test; one-sided). In plasma cfDNA profiles from cancer patients, MetDecode assigned the correct tissue-of-origin in 84.2% of cases. In conclusion, MetDecode can unravel alterations in the cfDNA pool components by accurately estimating the contribution of multiple tissues, while supplied with an imperfect reference atlas., Availability and Implementation: MetDecode is available at https://github.com/JorisVermeeschLab/MetDecode., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Recurrent cervical cancer is a life-threatening disease, with limited treatment options available when disease progression occurs after first-line combination therapy., Methods: We conducted a phase 3, multinational, open-label trial of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer. Patients were randomly assigned, in a 1:1 ratio, to receive tisotumab vedotin monotherapy (2.0 mg per kilogram of body weight every 3 weeks) or the investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed). The primary end point was overall survival., Results: A total of 502 patients underwent randomization (253 were assigned to the tisotumab vedotin group and 249 to the chemotherapy group); the groups were similar with respect to demographic and disease characteristics. The median overall survival was significantly longer in the tisotumab vedotin group than in the chemotherapy group (11.5 months [95% confidence interval {CI}, 9.8 to 14.9] vs. 9.5 months [95% CI, 7.9 to 10.7]), results that represented a 30% lower risk of death with tisotumab vedotin than with chemotherapy (hazard ratio, 0.70; 95% CI, 0.54 to 0.89; two-sided P = 0.004). The median progression-free survival was 4.2 months (95% CI, 4.0 to 4.4) with tisotumab vedotin and 2.9 months (95% CI, 2.6 to 3.1) with chemotherapy (hazard ratio, 0.67; 95% CI, 0.54 to 0.82; two-sided P<0.001). The confirmed objective response rate was 17.8% in the tisotumab vedotin group and 5.2% in the chemotherapy group (odds ratio, 4.0; 95% CI, 2.1 to 7.6; two-sided P<0.001). A total of 98.4% of patients in the tisotumab vedotin group and 99.2% in the chemotherapy group had at least one adverse event that occurred during the treatment period (defined as the period from day 1 of dose 1 until 30 days after the last dose); grade 3 or greater events occurred in 52.0% and 62.3%, respectively. A total of 14.8% of patients stopped tisotumab vedotin treatment because of toxic effects., Conclusions: In patients with recurrent cervical cancer, second- or third-line treatment with tisotumab vedotin resulted in significantly greater efficacy than chemotherapy. (Funded by Genmab and Seagen [acquired by Pfizer]; innovaTV 301 ClinicalTrials.gov number, NCT04697628.)., (Copyright © 2024 Massachusetts Medical Society.)

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10 -8 ) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10 -5 ). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Low-grade serous ovarian cancer (LGSOC) is a rare ovarian malignancy primarily affecting younger women and is characterized by an indolent growth pattern. It exhibits indolent growth and high estrogen/progesterone receptor expression, suggesting potential responsiveness to endocrine therapy. However, treatment efficacy remains limited due to the development of endocrine resistance. The mechanisms of resistance, whether primary or acquired, are still largely unknown and present a significant hurdle in achieving favorable treatment outcomes with endocrine therapy in these patients. In estrogen receptor-positive breast cancer, mechanisms of endocrine resistance have been largely explored and novel treatment strategies to overcome resistance have emerged. Considering the shared estrogen receptor positivity in LGSOC and breast cancer, we wanted to explore whether there are any parallel mechanisms of resistance and whether we can extend endocrine breast cancer treatments to LGSOC. This review aims to highlight the underlying molecular mechanisms possibly driving endocrine resistance in ovarian cancer, while also exploring the available therapeutic opportunities to overcome this resistance. By unraveling the potential pathways involved and examining emerging strategies, this review explores valuable insights for advancing treatment options and improving patient outcomes in LGSOC, which has limited therapeutic options available., Competing Interests: E.V.N. reports consulting fees from Regeneron, Oncoinvent, AstraZeneca, Roche, Seagen, Novartis, Merck, and Verastem. T.O. declares no conflicts of interest.

Background: Low-grade serous and endometrioid ovarian cancers and adult-type granulosa cell tumors are rare ovarian malignancies that show high estrogen receptor positivity. Recurrences of these subtypes of ovarian cancer are often treated with conventional chemotherapy, although response rates are disappointing., Primary Objective: To determine the overall response rate of the combination therapy of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancers., Study Hypothesis: The combination therapy of abemaciclib and letrozole will provide a clinically meaningful therapeutic benefit, with an overall response rate of >25%., Trial Design: This is a phase II, international, multicenter, open-label, single-arm study to evaluate the efficacy and safety of abemaciclib and letrozole in patients with advanced, recurrent, and/or metastatic estrogen receptor-positive, rare ovarian cancer. The study will follow a tandem two-stage design., Major Inclusion/exclusion Criteria: Patients must have histologically confirmed low-grade serous/endometrioid ovarian cancer or adult-type granulosa cell tumor with estrogen receptor positivity on immunohistochemistry. Patients need to have recurrent and measurable disease according to Radiologic Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A maximum of two prior lines of endocrine therapy are allowed, and patients cannot have previously received a cyclin-dependent kinase inhibitor. Patients with platinum-refractory disease are not allowed in any stage of the study., Primary Endpoint: Investigator-assessed confirmed overall response rate, defined as the proportion of patients with a complete or partial response according to RECIST v1.1., Sample Size: 40 to 100 patients will be included, depending on the results of the interim analysis. Patients will be included in Belgium, France and the Netherlands., Estimated Dates for Completing Accrual and Presenting Results: Patient recruitment will be completed by the end of 2025 and reporting of the final study results will be done by the end of 2027., Trial Registration Number: NCT05872204., Competing Interests: Competing interests: EVN reports consulting fees from Regeneron, Oncoinvent, AstraZeneca, Roche, Seagen, Novartis, Merck and Verastem; and receipt of study drug abemaciclib for this study from Eli Lilly. TVG reports grants/contracts from the Fund for Scientific Research-Flanders (FWO); consulting fees (paid to the institution) from AstraZeneca, Eisai, OncXerna Therapeutics, MSD, GSK, ImmunoGen, Seagen, Tubulis and Zentalis; honoraria (paid to the institution) from ImmunoGen, GSK, AstraZeneca; and meeting/travel support from Amgen, Pfizer, Roche, GSK, Novartis, ImmunoGen, MSD, PharmaMar and Sanofi-Aventis. FK reports grants/contracts from GSK, PharmaMar and AstraZeneca; consulting fees from GSK and PharmaMar; honoraria from GSK; expert testimony for GSK and AstraZeneca; meeting/travel support from PharmaMar and AstraZeneca; and advisory board for AstraZeneca. TB reports grants/contracts from Roche; honoraria from Novartis, AstraZeneca and Eli Lilly; and meeting/travel support from AstraZeneca, GSK and MSD. HD reports grants/contracts (paid to the institution) from Gilead; consulting fees (paid to the institution) from GSK and Gilead; honoraria (paid to the institution) from AstraZeneca, GSK, Eli Lilly, Gilead, Amgen, Roche, Leo Pharma, MSD, Daiichi Sannkyo and Teva Pharmaceuticals; meeting/travel support (paid to the institution) from GSK, AstraZeneca, Gilead, Roche, MSD, Pfizer, Teva Pharmaceuticals and PharmaMar; and advisory board (paid to the institution) for GSK, AstraZeneca, MSD, Menarini, Eli Lilly, Pfizer, Gilead, Seagen. FS reports consulting fees from AstraZeneca, GSK Tesaro and MSD; and honoraria from AstraZeneca, GSK Tesaro, MSD and Eisai. IB reports grants from Springer Healthcare and GSK; honoraria from Status Plus Gynaecongres; and participation on the DSMB of the Direct2 study (no payments).TO, ASVR and DL have no competing interests to disclose., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Purpose: Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease., Methods: This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control., Results: Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents., Conclusion: Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.