Efficacy and safety of durvalumab with olaparib in metastatic or recurrent endometrial cancer (phase II DOMEC trial)

Post, Cathalijne; Westermann, Anneke M.; Boere, Ingrid; Witteveen, Petronella O.; Ottevanger, Petronella B.; Sonke, Gabe S.; Lalisang, Roy I.; Putter, Hein; Kranenbarg, Elma Meershoek-Klein; Braak, Jeffrey P.B.M.; Creutzberg, Carien L.; Bosse, Tjalling; Kroep, Judith R.

doi:10.1016/j.ygyno.2022.02.025

Cited by 29 publications

(24 citation statements)

References 33 publications

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“…PARP inhibitors have achieved positive results in off-label treatments of EC cases 68. However, the treatment efficacy was not certainly good because of the heterogeneity of EC 69. In our study, we found that IRPRI could be used as a good predictive marker for PARP inhibitors since patients in the IRPRI-low group were more BRCA1/2 mutated and HRD deficient.…”

Section: Discussionmentioning

confidence: 58%

Tumor Microenvironment CD8 T and Treg Cells–related Genes Signature Distinguishes Distinct Prognosis and Targeted Therapies Response in Endometrial Cancer

Liu

Dong

Wang

et al. 2023

Journal of Immunotherapy

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Although most endometrial cancer (EC) patients have a favorable prognosis, the overall survival (OS) of metastatic and recurrent EC could hardly be improved by the current chemoradiotherapy. We aimed to reveal the tumor microenvironment immune infiltration characteristics to elucidate the underlying mechanism of EC progression and guide clinical decisions. In the Cancer Genome Atlas (TCGA) cohort, Kaplan-Meier survival curves confirmed Tregs and CD8 T cells were prognosis-protective factors in OS of EC (P < 0.05). Weighted gene coexpression network analysis identified 2 gene modules closely correlated with Tregs and CD8 T-cell infiltration. We randomly split the TCGA EC cohort into the training and testing cohorts at a ratio of 7:3. An immunerelated prognosis risk index (IRPRI), including NR3C1, E2F1, OTOG, TTK, PPP1R16B, and FOXP3, was established by univariate, Least Absolute Shrinkage and Selection Operator, and multivariate Cox regression with area under the curve > 0.67. Distinct clinical, immune, and mutation characteristics existed between IRPRI groups by multiomics analysis. Cell proliferation and DNA damage repair-related pathways were activated, and immune-related pathways were inactivated in the IRPRI-high group. Furthermore, patients in the IRPRI-high group had lower tumor mutation burden, programmed death-ligand 1 expression, and Tumor Immune Dysfunction and Exclusion scores, indicating a poor response to immune checkpoint inhibitors therapy (P < 0.05), which was also validated in the TCGA testing cohort and independent cohorts, GSE78200, GSE115821, and GSE168204. Also, the higher mutation frequencies of BRCA1, BRCA2, and genes enrolled in homologous recombination repair in the IRPRI-low group predicted a good response to PARP inhibitors. Finally, a nomogram integrating the IRPRI group and prognosis significant clinicopathological factors for EC OS prediction was developed and validated with good discrimination and calibration.

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Section: Discussionmentioning

confidence: 58%

Tumor Microenvironment CD8 T and Treg Cells–related Genes Signature Distinguishes Distinct Prognosis and Targeted Therapies Response in Endometrial Cancer

Liu

Dong

Wang

et al. 2023

Journal of Immunotherapy

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“…Preliminary results from early phase basket studies demonstrate a tolerable safety profile for the combination of PARPi and immune checkpoint inhibitors with varying antitumour activity across different tumour types [ 79 , 80 ]. In the TOPACIO study, which explored the combination therapy of PARPi and pembrolizumab, patients with advanced or metastatic unselected TNBC demonstrated an ORR of 21% (90% CI, 12–33%) with a DCR of 49% [ 81 ], while the recurrent ovarian cancer cohort demonstrated an ORR of 18% (90% CI = 11–29%) and a DCR of 65% [ 82 ].…”

Section: Overcoming Parp Inhibitor Resistance Through Combination Str...mentioning

confidence: 99%

PARP Inhibitors in Breast and Ovarian Cancer

Wang

Jie

Cheng

et al. 2023

Cancers

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Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most successful examples of clinical translation of targeted therapies in medical oncology, and this has been demonstrated by their effective management of BRCA1/BRCA2 mutant cancers, most notably in breast and ovarian cancers. PARP inhibitors target DNA repair pathways that BRCA1/2-mutant tumours are dependent upon. Inhibition of the key components of these pathways leads to DNA damage triggering subsequent critical levels of genomic instability, mitotic catastrophe and cell death. This ultimately results in a synthetic lethal relationship between BRCA1/2 and PARP, which underpins the effectiveness of PARP inhibitors. Despite the early and dramatic response seen with PARP inhibitors, patients receiving them often develop treatment resistance. To date, data from both clinical and preclinical studies have highlighted multiple resistance mechanisms to PARP inhibitors, and only by understanding these mechanisms are we able to overcome the challenges. The focus of this review is to summarise the underlying mechanisms underpinning treatment resistance to PARP inhibitors and to aid both clinicians and scientists to develop better clinically applicable assays to better select patients who would derive the greatest benefit as well as develop new novel/combination treatment strategies to overcome these mechanisms of resistance. With a better understanding of PARP inhibitor resistance mechanisms, we would not only be able to identify a subset of patients who are unlikely to benefit from therapy but also to sequence our treatment paradigm to avoid and overcome these resistance mechanisms.

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“…However, in the single-arm phase II DOMEC trial, the combination of durvalumab (anti-PD-L1) and olaparib (PARP inhibitor) did not meet the prespecified 50% 6-month progression-free survival in the overall population (median progression-free survival 3.4 months, 95% CI 2.8 to 6.2 months) nor in the dMMR cohort (median progressionfree survival 5.7 months, 95% CI 2.8 to NR). 19 Two trials, RUBY part 2 and DUO-E, are investigating the combination of platinumbased chemotherapy, immune checkpoint inhibitors, and PARP inhibitors in first-line treatment of advanced endometrial cancer (NCT03981796, NCT04269200). Additionally, avelumab, in combination with either talazoparib (PARP inhibitor) or axitinib (tyrosine kinase inhibitor), is being studied in patients with endometrial cancer based on mismatch repair status (NCT02912572).…”

Section: Immunotherapymentioning

confidence: 99%

Biomarker-driven therapy in endometrial cancer

Karpel

Slomovitz

Coleman

et al. 2023

Int J Gynecol Cancer

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This article reviews treatments and targets of interest in endometrial cancer by molecular subtype. The Cancer Genome Atlas (TCGA) classifies four molecular subtypes—mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H); copy number high (CNH)/p53abn; copy number low (CNL)/no specific molecular profile (NSMP); and POLEmut—which are validated and highly prognostic. Treatment consideration by subtype is now recommended. In March and April 2022, respectively, the US Food and Drug Administration (FDA) fully approved and the European Medicines Agency adopted a positive opinion recommending the anti-programmed cell death protein-1 (PD-1) antibody pembrolizumab for advanced/recurrent dMMR/MSI-H endometrial cancer which has progressed on or following a platinum-containing therapy. A second anti-PD-1, dostarlimab, received accelerated approval by the FDA and conditional marketing authorization by the European Medicines Agency in this group. The combination of pembrolizumab/lenvatinib for mismatch repair proficient/microsatellite stable endometrial cancer, including p53abn/CNH and NSMP/CNL, received accelerated FDA approval in conjunction with Australia’s Therapeutic Goods Administration and Health Canada in September 2019. The FDA and European Medicines Agency made full recommendations in July 2021 and October 2021. Trastuzumab is National Comprehensive Cancer Network (NCCN) compendium listed for human epidermal growth factor receptor-2-positive serous endometrial cancer, which is primarily within the p53abn/CNH subtype. In addition to hormonal therapy, maintenance therapy with selinexor (exportin-1 inhibitor) showed potential benefit inp53-wildtype cases in a subset analysis and is being investigated prospectively. Other treatment regimens being evaluated in NSMP/CNL are hormonal combinations with cyclin-dependent kinase 4/6 inhibitors and letrozole. Ongoing trials are evaluating immunotherapy in combination with frontline chemotherapy and other targeted agents. Treatment de-escalation is being evaluated in POLEmut cases given its favorable prognosis with or without adjuvant therapy. Molecular subtyping has important prognostic and therapeutic implications, and should guide patient management and clinical trial design in endometrial cancer, which is a molecularly driven disease.

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Efficacy and safety of durvalumab with olaparib in metastatic or recurrent endometrial cancer (phase II DOMEC trial)

Cited by 29 publications

References 33 publications

Tumor Microenvironment CD8 T and Treg Cells–related Genes Signature Distinguishes Distinct Prognosis and Targeted Therapies Response in Endometrial Cancer

Tumor Microenvironment CD8 T and Treg Cells–related Genes Signature Distinguishes Distinct Prognosis and Targeted Therapies Response in Endometrial Cancer

PARP Inhibitors in Breast and Ovarian Cancer

Biomarker-driven therapy in endometrial cancer

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