Pharmacodynamic effects of the PARP inhibitor talazoparib (MDV3800, BMN 673) in patients with BRCA-mutated advanced solid tumors.

Autor: Mittra A; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Bethesda, MD, 20892, USA.; Division of Medical Oncology, The Ohio State University, Columbus, OH, 43210, USA., Coyne GHOS; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Bethesda, MD, 20892, USA., Zlott J; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Bethesda, MD, 20892, USA., Kummar S; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Bethesda, MD, 20892, USA.; Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA., Meehan R; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Bethesda, MD, 20892, USA., Rubinstein L; Biometric Research Program, National Cancer Institute, Bethesda, MD, 20892, USA., Juwara L; Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Wilsker D; Clinical Pharmacodynamics Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Ji J; Clinical Pharmacodynamics Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Miller B; Clinical Pharmacodynamics Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Navas T; Clinical Pharmacodynamics Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.; Regeneron Pharmaceuticals, Tarrytown, NY, 10591, USA., Ferry-Galow KV; Clinical Pharmacodynamics Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Voth AR; Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Chang TC; Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Jiwani S; Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Parchment RE; Clinical Pharmacodynamics Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Doroshow JH; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Bethesda, MD, 20892, USA.; Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA., Chen AP; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Bethesda, MD, 20892, USA. chenali@mail.nih.gov.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2024 Mar; Vol. 93 (3), pp. 177-189. Date of Electronic Publication: 2023 Nov 27.
DOI: 10.1007/s00280-023-04600-0
Abstrakt: Purpose: Talazoparib is an inhibitor of the poly (ADP-ribose) polymerase (PARP) family of enzymes and is FDA-approved for patients with (suspected) deleterious germline BRCA1/2-mutated, HER2‑negative, locally advanced or metastatic breast cancer. Because knowledge of the pharmacodynamic (PD) effects of talazoparib in patients has been limited to studies of PARP enzymatic activity (PARylation) in peripheral blood mononuclear cells, we developed a study to assess tumoral PD response to talazoparib treatment (NCT01989546).
Methods: We administered single-agent talazoparib (1 mg/day) orally in 28-day cycles to adult patients with advanced solid tumors harboring (suspected) deleterious BRCA1 or BRCA2 mutations. The primary objective was to examine the PD effects of talazoparib; the secondary objective was to determine overall response rate (ORR). Tumor biopsies were mandatory at baseline and post-treatment on day 8 (optional at disease progression). Biopsies were analyzed for PARylation, DNA damage response (γH2AX), and epithelial‒mesenchymal transition.
Results: Nine patients enrolled in this trial. Four of six patients (67%) evaluable for the primary PD endpoint exhibited a nuclear γH2AX response on day 8 of treatment, and five of six (83%) also exhibited strong suppression of PARylation. A transition towards a more mesenchymal phenotype was seen in 4 of 6 carcinoma patients, but this biological change did not affect γH2AX or PAR responses. The ORR was 55% with the five partial responses lasting a median of six cycles.
Conclusion: Intra-tumoral DNA damage response and inhibition of PARP enzymatic activity were confirmed in patients with advanced solid tumors harboring BRCA1/2 mutations after 8 days of talazoparib treatment.
(© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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