Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial
Abstract Endometrial cancers are characterized by frequent alterations in the PI3K-AKT-mTor, IGF1 and DNA repair signaling pathways. Concomitant inhibition of these pathways was warranted. ENDOLA phase I/II trial (NCT02755844) was designed to assess the safety/efficacy of the triplet combination of...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56914-7 |
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| author | Max Piffoux Alexandra Leary Philippe Follana Cyril Abdeddaim Florence Joly Sylvie Bin Maxime Bonjour Anais Boulai Celine Callens Laurent Villeneuve Marine Alexandre Verane Schwiertz Gilles Freyer Manuel Rodrigues Benoit You |
| author_facet | Max Piffoux Alexandra Leary Philippe Follana Cyril Abdeddaim Florence Joly Sylvie Bin Maxime Bonjour Anais Boulai Celine Callens Laurent Villeneuve Marine Alexandre Verane Schwiertz Gilles Freyer Manuel Rodrigues Benoit You |
| author_sort | Max Piffoux |
| collection | DOAJ |
| description | Abstract Endometrial cancers are characterized by frequent alterations in the PI3K-AKT-mTor, IGF1 and DNA repair signaling pathways. Concomitant inhibition of these pathways was warranted. ENDOLA phase I/II trial (NCT02755844) was designed to assess the safety/efficacy of the triplet combination of the PARP inhibitor olaparib, metronomic cyclophosphamide (50 mg daily), and PI3K-AKT-mTor inhibitor metformin (1500 mg daily) in women with recurrent endometrial carcinomas. Olaparib dose-escalation (100-300 mg twice-a-day (bid)) was used to determine the recommended-phase II-trial-dose (RP2D, primary endpoint), followed by an expansion cohort to determine the non-progression rate at 10 weeks (NPR-10w, secondary endpoint). 31 patients were treated. Olaparib RP2D was defined as 300 mg bid. The tolerability was acceptable, and grade 3-4 adverse events (51% patients) were mainly hematological. The NPR-10w was 61.5%, and the median progression-free survival (mPFS) was 5.2 months. In a post-hoc analysis, when explored by molecular subtypes/alterations, longer PFS were observed in patients with tumors characterized by a non-specific-molecular-profile (NSMP, n = 4; mPFS, 9.1 months), and by both TP53 altered & high number of large genomic alterations (LGA ≥ 8)(n = 10, mPFS, 8.6 months)). The analyses about kinetics of circulating biomarkers and pharmacodynamic effects are not reported here. In total, the benefit/toxicity ratio of the all-oral olaparib/cyclophosphamide/metformin regimen was favorable in heavily pretreated patients with recurrent endometrial cancer. |
| format | Article |
| id | doaj-art-7cacbf4dd058417e9fa4529be86aa509 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-7cacbf4dd058417e9fa4529be86aa5092025-08-20T03:10:57ZengNature PortfolioNature Communications2041-17232025-02-011611910.1038/s41467-025-56914-7Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trialMax Piffoux0Alexandra Leary1Philippe Follana2Cyril Abdeddaim3Florence Joly4Sylvie Bin5Maxime Bonjour6Anais Boulai7Celine Callens8Laurent Villeneuve9Marine Alexandre10Verane Schwiertz11Gilles Freyer12Manuel Rodrigues13Benoit You14Medical Oncology, Hospices Civils de Lyon, EPSILYON, Lyon, France; GINECOMedical Oncology, Institut Gustave Roussy, Villejuif, France; GINECOCentre Antoine Lacassagne, Nice, France; GINECOCentre Oscar Lambret, Lille, France; GINECOCentre Francois Baclesse, Caen, France; GINECOPôle Santé Publique, Hospices Civils de LyonPôle Santé Publique, Hospices Civils de LyonGenetics Department, Institut Curie and Paris Sciences Lettres UniversityGenetics Department, Institut Curie and Paris Sciences Lettres UniversityPôle Santé Publique, Hospices Civils de LyonPôle Santé Publique, Hospices Civils de LyonPharmacy, Hospices Civils de LyonMedical Oncology, Hospices Civils de Lyon, EPSILYON, Lyon, France; GINECOMedical Oncology, Institut CurieMedical Oncology, Hospices Civils de Lyon, EPSILYON, Lyon, France; GINECOAbstract Endometrial cancers are characterized by frequent alterations in the PI3K-AKT-mTor, IGF1 and DNA repair signaling pathways. Concomitant inhibition of these pathways was warranted. ENDOLA phase I/II trial (NCT02755844) was designed to assess the safety/efficacy of the triplet combination of the PARP inhibitor olaparib, metronomic cyclophosphamide (50 mg daily), and PI3K-AKT-mTor inhibitor metformin (1500 mg daily) in women with recurrent endometrial carcinomas. Olaparib dose-escalation (100-300 mg twice-a-day (bid)) was used to determine the recommended-phase II-trial-dose (RP2D, primary endpoint), followed by an expansion cohort to determine the non-progression rate at 10 weeks (NPR-10w, secondary endpoint). 31 patients were treated. Olaparib RP2D was defined as 300 mg bid. The tolerability was acceptable, and grade 3-4 adverse events (51% patients) were mainly hematological. The NPR-10w was 61.5%, and the median progression-free survival (mPFS) was 5.2 months. In a post-hoc analysis, when explored by molecular subtypes/alterations, longer PFS were observed in patients with tumors characterized by a non-specific-molecular-profile (NSMP, n = 4; mPFS, 9.1 months), and by both TP53 altered & high number of large genomic alterations (LGA ≥ 8)(n = 10, mPFS, 8.6 months)). The analyses about kinetics of circulating biomarkers and pharmacodynamic effects are not reported here. In total, the benefit/toxicity ratio of the all-oral olaparib/cyclophosphamide/metformin regimen was favorable in heavily pretreated patients with recurrent endometrial cancer.https://doi.org/10.1038/s41467-025-56914-7 |
| spellingShingle | Max Piffoux Alexandra Leary Philippe Follana Cyril Abdeddaim Florence Joly Sylvie Bin Maxime Bonjour Anais Boulai Celine Callens Laurent Villeneuve Marine Alexandre Verane Schwiertz Gilles Freyer Manuel Rodrigues Benoit You Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial Nature Communications |
| title | Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial |
| title_full | Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial |
| title_fullStr | Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial |
| title_full_unstemmed | Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial |
| title_short | Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial |
| title_sort | olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced metastatic endometrial cancer the endola phase i ii trial |
| url | https://doi.org/10.1038/s41467-025-56914-7 |
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