Abstract CT006: Phase Ib expansion trial of the safety and efficacy of the oral ataxia telangiectasia and Rad3-related (ATR) inhibitor elimusertib in advanced solid tumors with DNA damage response (DDR) defects

Yap, Timothy A.; Tan, David; Stathis, Anastasios; Shapiro, Geoffrey I.; Iwasa, Satoru; Joerger, Markus; Zhang, Jingsong; Plummer, Ruth; Sawyer, Michael B.; Tan, Aaron C.; Castonguay, Vincent; Gabrail, Nashat; Matsubara, Nobuaki; Wilkinson, Gary; Ludwig, Matthias; Zhou, Yinghui; Merz, Claudia; Hreiki, Joseph; Sharma, Neelesh; Bono, Johann S. de

doi:10.1158/1538-7445.am2022-ct006

Cited by 13 publications

(12 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…WEE1 regulates cell cycle progression, whereas ATR intervenes in the DNA damage response. In 2 phase 1 studies, the combination of the ATR inhibitor camonsertib and low-dose PARP inhibitors (talazoparib, niraparib, or olaparib) showed an ORR of 13% in heavily pretreated patients with DDR-aberrant solid tumors, although only 1 of 17 patients with breast cancer achieved an objective response . The phase 2 VIOLETTE trial investigated olaparib alone, in combination with the ATR inhibitor ceralasertib or the WEE1 inhibitor adavosertib as second-line or third-line treatment for patients with unselected metastatic TNBC.…”

Section: Discussionmentioning

confidence: 99%

PARP Inhibitors for Breast Cancer Treatment

Morganti,

Marra,

De Angelis

et al. 2024

JAMA Oncol

View full text Add to dashboard Cite

ImportancePoly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors have revolutionized the treatment of patients with germline BRCA1/2-associated breast cancer, representing the first targeted therapy capable of improving outcomes in patients with hereditary tumors. However, resistance to PARP inhibitors occurs in almost all patients.ObservationsThis narrative review summarizes the biological rationale behind the use of PARP inhibitors in breast cancer, as well as the available evidence, recent progress, and potential future applications of these agents. Recent studies have shown that the benefit of PARP inhibitors extends beyond patients with germline BRCA1/2-associated metastatic breast cancer to patients with somatic BRCA1/2 variants and to those with germline PALB2 alterations. Moreover, these agents proved to be effective both in the metastatic and adjuvant settings. However, patients with metastatic breast cancer usually do not achieve the long-term benefit from PARP inhibitors observed in other tumor types. Mechanisms of resistance have been identified, but how to effectively target them is largely unknown. Ongoing research is investigating both novel therapeutics and new combination strategies to overcome resistance. PARP1-selective inhibitors, by sparing the hematological toxic effects induced by the PARP2 blockade, are promising agents to be combined with chemotherapy, antibody-drug conjugates, and other targeted therapies.Conclusions and RelevanceAlthough the efficacy of PARP inhibitors is well established, many questions persist. Future research should focus on identifying predictive biomarkers and therapeutic strategies to overcome resistance. Integrating well-designed translational efforts into all clinical studies is thereby crucial to laying the groundwork for future insights from ongoing research.

show abstract

Section: Discussionmentioning

confidence: 99%

PARP Inhibitors for Breast Cancer Treatment

Morganti,

Marra,

De Angelis

et al. 2024

JAMA Oncol

View full text Add to dashboard Cite

show abstract

“…Overall, the Clinical Benefit Rate of elimusertib was 35%. In patients with ATM loss, ORR was 8.9% and SD rate was 55.9% (84). Hematologic toxicity was the most frequent drug related adverse event.…”

Section: Other Inhibitors In Breast Cancers With Ddr Alterationsmentioning

confidence: 97%

“…Elimusertib (BAY1895344), a highly selective ATR inhibitor, demonstrated activity in a phase Ib trial against a range of advanced solid tumors with different putative deleterious DDR alterations (84). Among the 143 patients with advanced solid tumors included in the trial, 19 patients had HER2-negative breast cancer.…”

Section: Other Inhibitors In Breast Cancers With Ddr Alterationsmentioning

confidence: 99%

Homologous Recombination Defects and Mutations in DNA Damage Response (DDR) Genes BesidesBRCA1andBRCA2as Breast Cancer Biomarkers for PARP Inhibitors and Other DDR Targeting Therapies

Voutsadakis

Stravodimou

2023

Anticancer Res

View full text Add to dashboard Cite

Homologous recombination repair (HRR) is the cellular mechanism for error-free repair of double strand DNA (dsDNA) breaks. Cancer cells with mutations in both alleles of genes encoding for proteins involved in HRR, such as BRCA1 and BRCA2, have defects in the repair process. As a result, these cells repair dsDNA breaks with alternative mechanisms, such as non-homologous end joining. In breast cancers with germline mutations in BRCA1 and BRCA2 genes, HRR defects result in sensitivity to PARP inhibitors, drugs that interfere with the function of PARP enzyme and promote trapping of the enzyme on DNA and stalling of the process of repairing single strand breaks. HRR defects also lead to sensitivity to DNA damaging chemotherapy due to the inability of cells to repair chemotherapy induced DNA lesions. Besides germline mutations in BRCA1 and BRCA2, somatic mutations in these genes or germline and somatic mutations or other genetic and epigenetic alterations of other genes involved in homologous recombination (HR) may produce HRR defects leading to sensitivity to PARP inhibitors. However, studies are less conclusive, a fact that may relate to the common lack of bi-allelic loss of function in these cases, as opposed to cancers with germline BRCA1 or BRCA2 defects that usually acquire bi-allelic loss of function. In addition, there is heterogeneity between the different HRR genes and the severity of the resulting HRR defects, as measured by HR defect assays. This review article examines the landscape of HRR gene mutations in breast cancer and the possible therapeutic implications of HRR defects other than germline BRCA1 and BRCA2 mutations for targeted therapies. Identification of a wider range of breast cancers with HRR defects may expand the subset of patients that derive benefit from PARP inhibitors and other DDR-targeting drugs in the clinic.

show abstract

“…Seven patients (six with refractory malignant mesothelioma pleural or non-pleural) achieved RECIST v1.1 partial responses. 27 Another oral small-molecule inhibitor of TEAD palmitoylation, which is presently in phase I clinical trial evaluation (NCT05228015), is IK-930. In preclinical studies, IK-930 exhibited antitumour effects in mouse xenograft models featuring genetic alterations in the Hippo pathway.…”

Section: Targ E Ting the Yap/ Ta Z-te Ad S I G Nalling A Xis In Mpmmentioning

confidence: 99%

YAP/TAZ‐TEAD signalling axis: A new therapeutic target in malignant pleural mesothelioma

Papavassiliou,

Sofianidi,

Papavassiliou

2024

J Cellular Molecular Medi

View full text Add to dashboard Cite

The Hippo signalling pathway, a highly conserved signalling cassette, regulates organ size by controlling cell growth, apoptosis and stem cell self‐renewal. The tumourigenic potential of this pathway is largely attributed to the activity of YAP/TAZ, which activate the TEAD1‐4 transcription factors, leading to the expression of genes involved in cell proliferation and suppression of cell death. Aberrant regulation of the YAP/TAZ‐TEAD signalling axis is commonly observed in malignant pleural mesothelioma (MPM), an insidious neoplasm of the pleural tissue that lines the chest cavity and covers the lungs with poor prognosis. Given the limited effectiveness of current treatments, targeting the YAP/TAZ‐TEAD signalling cascade has emerged as a promising therapeutic strategy in MPM. Several inhibitors of the YAP/TAZ‐TEAD signalling axis are presently undergoing clinical development, with the goal of advancing them to clinical use in the near future.

show abstract

Abstract CT006: Phase Ib expansion trial of the safety and efficacy of the oral ataxia telangiectasia and Rad3-related (ATR) inhibitor elimusertib in advanced solid tumors with DNA damage response (DDR) defects

Cited by 13 publications

References 0 publications

PARP Inhibitors for Breast Cancer Treatment

PARP Inhibitors for Breast Cancer Treatment

Homologous Recombination Defects and Mutations in DNA Damage Response (DDR) Genes BesidesBRCA1andBRCA2as Breast Cancer Biomarkers for PARP Inhibitors and Other DDR Targeting Therapies

YAP/TAZ‐TEAD signalling axis: A new therapeutic target in malignant pleural mesothelioma

Contact Info

Product

Resources

About