Effectiveness and safety of poly (ADP-ribose) polymerase inhibitors in cancer therapy: A systematic review and meta-analysis

Bao, Zhengqiang; Cao, Chao; Geng, Xinwei; Tian, Bo; Wu, Yanping; Zhang, Chao; Chen, Zhihua; Wen, Li; Shen, Huahao; Ying, Songmin

doi:10.18632/oncotarget.5367

Cited by 32 publications

(31 citation statements)

References 51 publications

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“…The safety profile of PARP inhibitors is generally consistent across the different agents, with the primary toxicity being clinically manageable myelosuppression. Additional toxicities include mild-to-moderate gastrointestinal toxicity (i.e., nausea, vomiting, diarrhea, and abdominal pain) and fatigue (16). Three of the 83 evaluable patients from our study discontinued therapy for a drug-related toxicity, suggesting that most toxicity could be managed with supportive care.…”

Section: Discussionmentioning

confidence: 94%

A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO)

Turner

Telli

Rugo

et al. 2019

Clinical Cancer Research

115

108

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Purpose: To assess talazoparib activity in germline BRCA1/2 mutation carriers with advanced breast cancer. Patients and Methods: ABRAZO (NCT02034916) was a two-cohort, two-stage, phase II study of talazoparib (1 mg/day) in germline BRCA mutation carriers with a response to prior platinum with no progression on or within 8 weeks of the last platinum dose (cohort 1) or !3 platinumfree cytotoxic regimens (cohort 2) for advanced breast cancer. Primary endpoint was confirmed objective response rate (ORR) by independent radiological assessment. Results: We enrolled 84 patients (cohort 1, n ¼ 49; cohort 2, n ¼ 35) from May 2014 to February 2016. Median age was 50 (range, 31-75) years. Triple-negative breast cancer (TNBC) incidence was 59% (cohort 1) and 17% (cohort 2). Median number of prior cytotoxic regimens for advanced breast cancer was two and four, respectively. Confirmed ORR was 21% [95% confidence interval (CI), 10-35; cohort 1] and 37% [95% CI, 22-55; cohort 2]. Median duration of response was 5.8 and 3.8 months, respectively. Confirmed ORR was 23% (BRCA1), 33% (BRCA2), 26% (TNBC), and 29% (hormone receptorpositive). The most common all-grade adverse events (AE) included anemia (52%), fatigue (45%), and nausea (42%). Talazoparib-related AEs led to drug discontinuation in 3 (4%) patients. In an exploratory analysis, longer platinum-free interval was associated with higher response rate in cohort 1 (0% ORR with interval <8 weeks; 47% ORR with interval >6 months). Conclusions: Talazoparib exhibited promising antitumor activity in patients with advanced breast cancer and germline BRCA mutation.

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Section: Discussionmentioning

confidence: 94%

A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO)

Turner

Telli

Rugo

et al. 2019

Clinical Cancer Research

115

108

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“…Unfortunately, the first PARP inhibitor in a clinical trial did not inhibit PARP at the clinical doses [ 239 ]. Nevertheless, a meta-analysis of clinical studies of BRCA-PARP synthetic lethality in combination with various chemotherapeutic agents supports the efficacy of PARP inhibitors in improving progression-free survival, though overall survival was not significantly improved [ 240 ]. Fewer studies have combined the synthetic lethal approach with radiotherapy (reviewed in [ 241 , 242 ]), and the outcomes have not been published yet.…”

Section: Targets For Radiosensitizationmentioning

confidence: 99%

Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization

Maier

Hartmann

Wenz

et al. 2016

IJMS

329

259

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During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells and, secondly, the radiation-induced damage of normal tissue cells located in the field of ionizing radiation. These limitations demand the development of drugs for either radiosensitization of tumor cells or radioprotection of normal tissue cells. In order to identify potential targets, a detailed understanding of the cellular pathways involved in radiation response is an absolute requirement. This review describes the most important pathways of radioresponse and several key target proteins for radiosensitization.

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“…Cells deficient in homologous recombination cannot accurately repair these breaks, leading to genetic instability, chromosome rearrangement, and cell death (2). This synthetic lethality has proven effective for improving progression-free survival in patients with homologous repair-deficient BRCA mutations (3). PARP inhibitors have also been shown to trap PARP-1 and PARP-2 on DNA (4), thereby forming PARP-DNA complexes which are thought to be responsible for the synergism seen with PARP inhibition and alkylating agents.…”

Section: Introductionmentioning

confidence: 99%

Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation

Ven

Tangutoori

Baldwin

et al. 2017

Molecular Cancer Therapeutics

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The use of PARP inhibitors in combination with radiation therapy is a promising strategy to locally enhance DNA-damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation-sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of Olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral Olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13 week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, this data suggests that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions.

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Effectiveness and safety of poly (ADP-ribose) polymerase inhibitors in cancer therapy: A systematic review and meta-analysis

Cited by 32 publications

References 51 publications

A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO)

A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO)

Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization

Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation

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