Publications
321 results found
Xu Y, Spear S, Ma Y, et al., 2023, Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma, Cell Reports, Vol: 42, ISSN: 2211-1247
Ovarian high-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer with limited therapeutic options and a poor prognosis. In recent years, poly-ADP ribose polymerase (PARP) inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Indisulam (E7070) has been identified as a molecular glue that brings together splicing factor RBM39 and DCAF15 E3 ubiquitin ligase resulting in polyubiquitination, degradation, and subsequent RNA splicing defects. In this work, we demonstrate that the loss of RBM39 induces splicing defects in key DNA damage repair genes in ovarian cancer, leading to increased sensitivity to cisplatin and various PARP inhibitors. The addition of indisulam also improved olaparib response in mice bearing PARP inhibitor-resistant tumors. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improve PARP inhibitor response in ovarian HGSC.
Sauer CM, Hall JA, Couturier D-L, et al., 2023, Molecular landscape and functional characterization of centrosome amplification in ovarian cancer., Nat Commun, Vol: 14
High-grade serous ovarian carcinoma (HGSOC) is characterised by poor outcome and extreme chromosome instability (CIN). Therapies targeting centrosome amplification (CA), a key mediator of chromosome missegregation, may have significant clinical utility in HGSOC. However, the prevalence of CA in HGSOC, its relationship to genomic biomarkers of CIN and its potential impact on therapeutic response have not been defined. Using high-throughput multi-regional microscopy on 287 clinical HGSOC tissues and 73 cell lines models, here we show that CA through centriole overduplication is a highly recurrent and heterogeneous feature of HGSOC and strongly associated with CIN and genome subclonality. Cell-based studies showed that high-prevalence CA is phenocopied in ovarian cancer cell lines, and that high CA is associated with increased multi-treatment resistance; most notably to paclitaxel, the commonest treatment used in HGSOC. CA in HGSOC may therefore present a potential driver of tumour evolution and a powerful biomarker for response to standard-of-care treatment.
Lightley J, Kumar S, Lim MQ, et al., 2023, <i>openFrame</i>: A modular, sustainable, open microscopy platform with single-shot, dual-axis optical autofocus module providing high precision and long range of operation, JOURNAL OF MICROSCOPY, ISSN: 0022-2720
Smith P, Bradley T, Gavarró LM, et al., 2023, Author Correction: The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma., Nat Commun, Vol: 14
Giannone G, McNeish IA, Banerjee S, 2023, Biomarker analysis of vistusertib plus paclitaxel regimen - reply, JAMA Oncology, ISSN: 2374-2437
Corbaux P, You B, Glasspool RM, et al., 2023, Survival and modelled cancer antigen-125 ELIMination rate constant K score in ovarian cancer patients in first- line before poly(ADP-ribose) polymerase inhibitor era: A Gynaecologic Cancer Intergroup meta-analysis, EUROPEAN JOURNAL OF CANCER, Vol: 191, ISSN: 0959-8049
Nikolatou K, Sandilands E, Román-Fernández A, et al., 2023, PTEN deficiency exposes a requirement for an ARF GTPase module in integrin-dependent invasion in ovarian cancer., The EMBO Journal, Vol: 42, Pages: 1-25, ISSN: 0261-4189
Dysregulation of the PI3K/AKT pathway is a common occurrence in high-grade serous ovarian carcinoma (HGSOC), with the loss of the tumour suppressor PTEN in HGSOC being associated with poor prognosis. The cellular mechanisms of how PTEN loss contributes to HGSOC are largely unknown. We here utilise time-lapse imaging of HGSOC spheroids coupled to a machine learning approach to classify the phenotype of PTEN loss. PTEN deficiency induces PI(3,4,5)P3-rich and -dependent membrane protrusions into the extracellular matrix (ECM), resulting in a collective invasion phenotype. We identify the small GTPase ARF6 as a crucial vulnerability of HGSOC cells upon PTEN loss. Through a functional proteomic CRISPR screen of ARF6 interactors, we identify the ARF GTPase-activating protein (GAP) AGAP1 and the ECM receptor β1-integrin (ITGB1) as key ARF6 interactors in HGSOC regulating PTEN loss-associated invasion. ARF6 functions to promote invasion by controlling the recycling of internalised, active β1-integrin to maintain invasive activity into the ECM. The expression of the CYTH2-ARF6-AGAP1 complex in HGSOC patients is inversely associated with outcome, allowing the identification of patient groups with improved versus poor outcome. ARF6 may represent a therapeutic vulnerability in PTEN-depleted HGSOC.
Marks ZRC, Campbell N, Mangan N, et al., 2023, Interferon-ε is a tumour suppressor and restricts ovarian cancer, NATURE, Vol: 620, Pages: 1063-+, ISSN: 0028-0836
Hasan AMM, Cremaschi P, Wetterskog D, et al., 2023, Copy number architectures define treatment-mediated selection of lethal prostate cancer clones, Nature Communications, Vol: 14, Pages: 1-16, ISSN: 2041-1723
Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance (p-values 3.07 × 10-8 and 6.4 × 10-4). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories.
Smith P, Bradley T, Gavarró LM, et al., 2023, The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma, Nature Communications, Vol: 14, Pages: 1-15, ISSN: 2041-1723
The drivers of recurrence and resistance in ovarian high grade serous carcinoma remain unclear. We investigate the acquisition of resistance by collecting tumour biopsies from a cohort of 276 women with relapsed ovarian high grade serous carcinoma in the BriTROC-1 study. Panel sequencing shows close concordance between diagnosis and relapse, with only four discordant cases. There is also very strong concordance in copy number between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic copy number alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Copy number signatures are strongly correlated with immune cell infiltration, whilst diagnosis samples from patients with primary platinum resistance have increased rates of CCNE1 and KRAS amplification and copy number signature 1 exposure. Our data show that the ovarian high grade serous carcinoma genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers.
Cunnea P, Curry EW, Christie EL, et al., 2023, Spatial and temporal intra-tumoral heterogeneity in advanced HGSOC: implications for surgical and clinical outcomes, Cell Reports Medicine, Vol: 4, Pages: 1-20, ISSN: 2666-3791
Limited evidence exists on the impact of spatial and temporal heterogeneity of high-grade serous ovarian cancer (HGSOC) on tumor evolution, clinical outcomes, and surgical operability. We perform systematic multi-site tumor mapping at presentation and matched relapse from 49 high-tumor-burden patients, operated up front. From SNP array-derived copy-number data, we categorize dendrograms representing tumor clonal evolution as sympodial or dichotomous, noting most chemo-resistant patients favor simpler sympodial evolution. Three distinct tumor evolutionary patterns from primary to relapse are identified, demonstrating recurrent disease may emerge from pre-existing or newly detected clones. Crucially, we identify spatial heterogeneity for clinically actionable homologous recombination deficiency scores and for poor prognosis biomarkers CCNE1 and MYC. Copy-number signature, phenotypic, proteomic, and proliferative-index heterogeneity further highlight HGSOC complexity. This study explores HGSOC evolution and dissemination across space and time, its impact on optimal surgical cytoreductive effort and clinical outcomes, and its consequences for clinical decision-making.
Samani A, Bennett R, Eremeishvili K, et al., 2023, Corrigendum to 'Glomerular filtration rate estimation for carboplatin dosing in patients with gynaecological cancers': [ESMO Open volume 7 (2022) 10.1016/j.esmoop.2022.100401]., ESMO Open, Vol: 8, Pages: 1-1, ISSN: 2059-7029
Morgan RD, Clamp AR, Barnes BM, et al., 2023, Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: a multi-national observational study, International Journal of Gynecological Cancer, Vol: 33, Pages: 1253-1259, ISSN: 1048-891X
OBJECTIVE: Olaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year of routine homologous recombination deficiency testing in the National Health Service (NHS) in England, Wales, and Northern Ireland between April 2021 and April 2022. METHODS: The Myriad myChoice companion diagnostic was used to test DNA extracted from formalin-fixed, paraffin-embedded tumor tissue in women with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumors with homologous recombination deficiency were those with a BRCA1/2 mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network. RESULTS: The myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwent BRCA1/2 and GIS testing, respectively. All complete and partial assay failures occurred due to low tumor cellularity and/or low tumor DNA yield. 385 tumors (16%) contained a BRCA1/2 mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to be BRCA1/2 wild-type (n=510) than BRCA1/2 mutant (n=304). The distribution of GIS was bimodal, with BRCA1/2 mutant tumors having a higher mean score than BRCA1/2 wild-type tumors (61 vs 33, respectively, χ2 test p<0.0001). CONCLUSION: This is the largest real-world evaluation of homologous recombination deficiency testing in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is important to select tumor tissue with adequate tumor content and quality to reduce the risk of assay failure. The rapid uptake of testing across England, Wales, and Northern Ireland demonstrates the power of centralized NHS funding, center specializat
Plummer R, Sodergren M, Ryan B, et al., 2023, MTL-CEBPA in combination with pembrolizumab converts an immune desert to an inflamed TME in solid tumors resistant to checkpoint blockade, 114th Annual Meeting of the American Association for Cancer Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Lau TS, Chan LKY, Man GCW, et al., 2023, Supplementary Figures and Legends from Paclitaxel Induces Immunogenic Cell Death in Ovarian Cancer via TLR4/IKK2/SNARE-Dependent Exocytosis
<jats:p><p>All Supplementary Figures and their respective legends.</p></jats:p>
Lau TS, Chan LKY, Man GCW, et al., 2023, Data from Paclitaxel Induces Immunogenic Cell Death in Ovarian Cancer via TLR4/IKK2/SNARE-Dependent Exocytosis
<jats:p><div>Abstract<p>Emerging evidence shows that the efficacy of chemotherapeutic drugs is reliant on their capability to induce immunogenic cell death (ICD), thus transforming dying tumor cells into antitumor vaccines. We wanted to uncover potential therapeutic strategies that target ovarian cancer by having a better understanding of the standard-of-care chemotherapy treatment. Here, we showed in ovarian cancer that paclitaxel induced ICD-associated damage-associated molecular patterns (DAMP, such as CALR exposure, ATP secretion, and HMGB1 release) <i>in vitro</i> and elicited significant antitumor responses in tumor vaccination assays <i>in vivo</i>. Paclitaxel-induced TLR4 signaling was essential to the release of DAMPs, which led to the activation of NF-κB–mediated CCL2 transcription and IkappaB kinase 2–mediated SNARE-dependent vesicle exocytosis, thus exposing CALR on the cell surface. Paclitaxel induced endoplasmic reticulum stress, which triggered protein kinase R–like ER kinase activation and eukaryotic translation initiation factor 2α phosphorylation independent of TLR4. Paclitaxel chemotherapy induced T-cell infiltration in ovarian tumors of the responsive patients; CALR expression in primary ovarian tumors also correlated with patients' survival and patient response to chemotherapy. These findings suggest that the effectiveness of paclitaxel relied upon the activation of antitumor immunity through ICD via TLR4 and highlighted the importance of CALR expression in cancer cells as an indicator of response to paclitaxel chemotherapy in ovarian cancer.</p></div></jats:p>
Lau TS, Chan LKY, Man GCW, et al., 2023, Supplementary Figures and Legends from Paclitaxel Induces Immunogenic Cell Death in Ovarian Cancer via TLR4/IKK2/SNARE-Dependent Exocytosis
<jats:p><p>All Supplementary Figures and their respective legends.</p></jats:p>
Lau TS, Chan LKY, Man GCW, et al., 2023, Supplementary Table S1 from Paclitaxel Induces Immunogenic Cell Death in Ovarian Cancer via TLR4/IKK2/SNARE-Dependent Exocytosis
<jats:p><p>Supplementary Table S1</p></jats:p>
Lau TS, Chan LKY, Man GCW, et al., 2023, Supplementary Table S1 from Paclitaxel Induces Immunogenic Cell Death in Ovarian Cancer via TLR4/IKK2/SNARE-Dependent Exocytosis
<jats:p><p>Supplementary Table S1</p></jats:p>
Lau TS, Chan LKY, Man GCW, et al., 2023, Data from Paclitaxel Induces Immunogenic Cell Death in Ovarian Cancer via TLR4/IKK2/SNARE-Dependent Exocytosis
<jats:p><div>Abstract<p>Emerging evidence shows that the efficacy of chemotherapeutic drugs is reliant on their capability to induce immunogenic cell death (ICD), thus transforming dying tumor cells into antitumor vaccines. We wanted to uncover potential therapeutic strategies that target ovarian cancer by having a better understanding of the standard-of-care chemotherapy treatment. Here, we showed in ovarian cancer that paclitaxel induced ICD-associated damage-associated molecular patterns (DAMP, such as CALR exposure, ATP secretion, and HMGB1 release) <i>in vitro</i> and elicited significant antitumor responses in tumor vaccination assays <i>in vivo</i>. Paclitaxel-induced TLR4 signaling was essential to the release of DAMPs, which led to the activation of NF-κB–mediated CCL2 transcription and IkappaB kinase 2–mediated SNARE-dependent vesicle exocytosis, thus exposing CALR on the cell surface. Paclitaxel induced endoplasmic reticulum stress, which triggered protein kinase R–like ER kinase activation and eukaryotic translation initiation factor 2α phosphorylation independent of TLR4. Paclitaxel chemotherapy induced T-cell infiltration in ovarian tumors of the responsive patients; CALR expression in primary ovarian tumors also correlated with patients' survival and patient response to chemotherapy. These findings suggest that the effectiveness of paclitaxel relied upon the activation of antitumor immunity through ICD via TLR4 and highlighted the importance of CALR expression in cancer cells as an indicator of response to paclitaxel chemotherapy in ovarian cancer.</p></div></jats:p>
Sokol ES, Madison RW, Jin DX, et al., 2023, Exploration of a novel HRD signature (HRDsig) as a biomarker for rucaparib benefit in ARIEL2, 114th Annual Meeting of the American Association for Cancer Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Kallemeijn WW, Spear S, Walton J, et al., 2023, From foe to friend: <i>In vivo</i> reprogramming of tumor-associated macrophages to an anti-cancer phenotype by modulating <i>N</i>-myristoyltransferase activity, 114th Annual Meeting of the American Association for Cancer Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Colomban O, Clamp A, Cook A, et al., 2023, Benefit From Fractionated Dose-Dense Chemotherapy in Patients With Poor Prognostic Ovarian Cancer: ICON-8 Trial., JCO Clin Cancer Inform, Vol: 7
PURPOSE: An international meta-analysis identified a group of patients with advanced epithelial ovarian cancer (EOC) with a very poor survival because of two unfavorable features: (1) a poor chemosensitivity defined by an unfavorable modeled CA-125 ELIMination rate constant K (KELIM) score <1.0 with the online calculator CA-125-Biomarker Kinetics, and (2) an incomplete debulking surgery. We assumed that patients belonging to this poor prognostic group would benefit from a fractionated densified chemotherapy regimen. METHODS: The data set of ICON-8 phase III trial (ClinicalTrials.gov identifier: NCT01654146), where patients with EOC were treated with the standard three-weekly, or the weekly dose-dense, carboplatin-paclitaxel regimens and debulking primary surgery (immediate primary surgery [IPS] or delayed primary [or interval] surgery [DPS]), was investigated. The association between treatment arm efficacy, standardized KELIM (scored as favorable ≥1.0, or unfavorable <1.0), and surgery completeness was assessed by univariate/multivariate analyses in IPS and DPS cohorts. RESULTS: Of 1,566 enrolled patients, KELIM was calculated with the online model in 1,334 with ≥3 CA-125 available values (85%). As previously reported, both KELIM and surgery completeness were complementary prognostic covariates, and could be combined into three prognostic groups with large OS differences: (1) good if favorable KELIM and complete surgery; (2) intermediate if either unfavorable KELIM or incomplete surgery; and (3) poor if unfavorable KELIM and incomplete surgery. Weekly dose-dense chemotherapy was associated with PFS/OS improvement in the poor prognostic group in both the IPS cohort (PFS: hazard ratio [HR], 0.50; 95% CI, 0.31 to 0.79; OS: HR, 0.58; 95% CI, 0.35 to 0.95) and the DPS cohort (PFS: HR, 0.53; 95% CI, 0.37 to 0.76; OS: HR, 0.57; 95% CI, 0.39 to 0.82). CONCLUSION: Fractionated dose-dense chemotherapy might be beneficial for patients belonging to the poor prognost
Li C, Course MM, McNeish IA, et al., 2023, Supplementary Data from Prophylactic <i>In Vivo</i> Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models
<jats:p><p>Supplementary Fig. S1. Rat Neu is expressed in MMC cells. Supplementary Fig. S2. Gating strategy used for immunophenotyping. Supplementary Fig. S3. Immunophenotyping of GFP+ cells in the bone marrow and spleen (MMC model). Supplementary Fig.S4. GFP expression in tumor-infiltrating leukocytes after in vivo HSPC transduction (TC-1 model). Supplementary Fig. S5. Validation of miR-423-5p expression by Northern blot. Supplementary Fig.S6. miRNA423-5p expression in humans. Supplementary Fig. S7. Autoimmune reactions in animals sacrificed at day 17 at the peak of aPDL1-gamma1, before reversal of tumor growth. Supplementary Fig. S8. Effect of anti-PDL1 monoclonal antibody therapy in neu-transgenic mice with MMC tumors. Supplementary Fig. S9. Effect of in vivo HSC transduction on hemopoiesis. Suppl. Methods</p></jats:p>
Li C, Course MM, McNeish IA, et al., 2023, Supplementary Data from Prophylactic <i>In Vivo</i> Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models
<jats:p><p>Supplementary Fig. S1. Rat Neu is expressed in MMC cells. Supplementary Fig. S2. Gating strategy used for immunophenotyping. Supplementary Fig. S3. Immunophenotyping of GFP+ cells in the bone marrow and spleen (MMC model). Supplementary Fig.S4. GFP expression in tumor-infiltrating leukocytes after in vivo HSPC transduction (TC-1 model). Supplementary Fig. S5. Validation of miR-423-5p expression by Northern blot. Supplementary Fig.S6. miRNA423-5p expression in humans. Supplementary Fig. S7. Autoimmune reactions in animals sacrificed at day 17 at the peak of aPDL1-gamma1, before reversal of tumor growth. Supplementary Fig. S8. Effect of anti-PDL1 monoclonal antibody therapy in neu-transgenic mice with MMC tumors. Supplementary Fig. S9. Effect of in vivo HSC transduction on hemopoiesis. Suppl. Methods</p></jats:p>
Li C, Course MM, McNeish IA, et al., 2023, Data from Prophylactic <i>In Vivo</i> Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models
<jats:p><div>Abstract<p>Population-wide testing for cancer-associated mutations has established that more than one-fifth of ovarian and breast carcinomas are associated with inherited risk. Salpingo-oophorectomy and/or mastectomy are currently the only effective options offered to women with high-risk germline mutations. Our goal here is to develop a long-lasting approach that provides immunoprophylaxis for mutation carriers. Our approach leverages the fact that at early stages, tumors recruit hematopoietic stem/progenitor cells (HSPC) from the bone marrow and differentiate them into tumor-supporting cells. We developed a technically simple technology to genetically modify HSPCs <i>in vivo</i>. The technology involves HSPC mobilization and intravenous injection of an integrating HDAd5/35++ vector. <i>In vivo</i> HSPC transduction with a GFP-expressing vector and subsequent implantation of syngeneic tumor cells showed >80% GFP marking in tumor-infiltrating leukocytes. To control expression of transgenes, we developed a miRNA regulation system that is activated only when HSPCs are recruited to and differentiated by the tumor. We tested our approach using the immune checkpoint inhibitor anti-PD-L1-γ1 as an effector gene. In <i>in vivo</i> HSPC-transduced mice with implanted mouse mammary carcinoma (MMC) tumors, after initial tumor growth, tumors regressed and did not recur. Conventional treatment with an anti-PD-L1 mAb had no significant antitumor effect, indicating that early, self-activating expression of anti-PD-L1-γ1 can overcome the immunosuppressive environment in MMC tumors. The efficacy and safety of this approach was further validated in an ovarian cancer model with typical germline mutations (ID8 p53<sup>−/−</sup> brca2<sup>−/−</sup>), both in a
Banerjee S, Giannone G, Clamp AR, et al., 2023, Efficacy and safety of weekly paclitaxel plus vistusertib vs paclitaxel alone in patients with platinum-resistant ovarian high-grade serous carcinoma: the octopus multicenter, phase 2, randomized clinical trial., JAMA Oncology, Vol: 9, Pages: 675-682, ISSN: 2374-2437
IMPORTANCE: Patients with platinum-resistant or refractory ovarian high-grade serous carcinoma (PR-HGSC) have a poor prognosis and few therapeutic options. Preclinical studies support targeting PI3K/AKT/mTOR signaling in this setting, and a phase 1 study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel showed activity. OBJECTIVE: To evaluate whether the addition of vistusertib to weekly paclitaxel improves clinical outcomes in patients with PR-HGSC. DESIGN, SETTING, AND PARTICIPANTS: This phase 2, double-blind, placebo-controlled multicenter randomized clinical trial recruited patients from UK cancer centers between January 2016 and March 2018. Patients with PR-HGSC of ovarian, fallopian tube, or primary peritoneal origin and with measurable or evaluable disease (Response Evaluation Criteria in Solid Tumors version 1.1 and/or Gynecological Cancer Intergroup cancer antigen 125 criteria) were eligible. There were no restrictions on number of lines of prior therapy. Data analysis was performed from May 2019 to January 2022. INTERVENTIONS: Patients were randomized (1:1) to weekly paclitaxel (80 mg/m2 days 1, 8, and 15 of a 28-day cycle) plus oral vistusertib (50 mg twice daily) or placebo. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intention-to-treat population. Secondary end points included response rate, overall survival, and quality of life. RESULTS: A total of 140 patients (median [range] age, 63 [36-86] years; 17.9% with platinum-refractory disease; 53.6% with ≥3 prior therapies) were randomized. In the paclitaxel plus vistusertib vs paclitaxel plus placebo groups, there was no difference in progression-free survival (median, 4.5 vs 4.1 months; hazard ratio [HR], 0.84; 80% CI, 0.67-1.07; 1-sided P = .18), overall survival (median, 9.7 vs 11.1 months; HR, 1.21; 80% CI, 0.91-1.60) or response rate (odds ratio, 0.86; 80% CI, 0.55-1.36). Grade 3 to 4 adverse events were 41.2% (wee
Colomban O, Swisher EM, Kristeleit R, et al., 2023, Mathematical modeling of the early modeled CA-125 longitudinal kinetics (KELIM-PARP) as a pragmatic indicator of rucaparib efficacy in patients with recurrent ovarian carcinoma in ARIEL2 & STUDY 10, EBIOMEDICINE, Vol: 89, ISSN: 2352-3964
Monk BJ, Fujiwara K, O'Malley DM, et al., 2023, The long-lasting challenge of predicting response to poly (ADP-ribose) polymerase inhibitors Reply, JOURNAL OF CLINICAL ONCOLOGY, Vol: 41, Pages: 936-938, ISSN: 0732-183X
Sundar S, Nordin A, Morrison J, et al., 2023, British Gynaecological Cancer Society Recommendations for Evidence Based, Population Data Derived Quality Performance Indicators for Ovarian Cancer, CANCERS, Vol: 15
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