PARP inhibitors: Clinical utility and possibilities of overcoming resistance

Bitler, Benjamin G.; Watson, Zachary L.; Wheeler, Lindsay J.; Behbakht, Kian

doi:10.1016/j.ygyno.2017.10.003

Cited by 181 publications

(182 citation statements)

References 68 publications

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“…The DNA damage repair (DDR) pathway is regulated by poly (ADP‐ribose) polymerase (PARP), and inhibition of PARP in DDR‐deficient cells leads to accumulation of irreparable DNA damage and cell death . PARP inhibitors have been approved for a variety of cancers with mutations in DNA repair genes . Talazoparib is a PARP inhibitor that inhibits PARP1/PARP2 and traps PARP on DNA, which can prevent DNA damage repair and result in cell death in cells with DDR gene mutations .…”

Section: Introductionmentioning

confidence: 99%

“…1 PARP inhibitors have been approved for a variety of cancers with mutations in DNA repair genes. 2 Talazoparib is a PARP inhibitor that inhibits PARP1/PARP2 and traps PARP on DNA, which can prevent DNA damage repair and result in cell death in cells with DDR gene mutations. 3 Talazoparib was approved by the United States Food and Drug Administration for treatment of patients with deleterious or suspected deleterious germline breast cancer susceptibility genes (BRCA)-mutated human epidermal growth factor receptor 2 (HER2)-negative locally advanced/metastatic breast cancer 4 based on results from the pivotal Phase 3 EMBRACA study, which showed statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs physician's choice of chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the effect of P‐glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours

Elmeliegy

Làng

Smolyarchuk

et al. 2020

Brit J Clinical Pharma

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Aims In vitro data show that talazoparib is a substrate for P‐glycoprotein (P‐gp) and breast cancer resistance protein transporters. This open‐label, 2‐arm, drug–drug interaction Phase 1 study in patients with advanced solid tumours assessed the effect of a P‐gp inhibitor (itraconazole) and a P‐gp inducer (rifampicin) on the pharmacokinetics of a single dose of talazoparib. The safety and tolerability of a single dose of talazoparib with and without itraconazole or rifampicin were also assessed. Methods Thirty‐six patients were enrolled (Arm A [itraconazole], n = 19; Arm B [rifampicin], n = 17). Patients in both arms received 2 single oral doses of talazoparib (0.5 mg, Arm A; 1 mg, Arm B) alone and with multiple daily oral doses of itraconazole (Arm A) or rifampicin (Arm B). Results Coadministration of itraconazole and talazoparib increased talazoparib area under the plasma concentration–time profile from time 0 extrapolated to infinity by ~56% and maximum observed plasma concentration by ~40% relative to talazoparib alone. Coadministration of rifampicin and talazoparib increased talazoparib maximum observed plasma concentration by approximately 37% (geometric mean ratio 136.6% [90% confidence interval 103.2–180.9]); area under the curve was not affected relative to talazoparib alone (geometric mean ratio 102.0% [90% confidence interval 94.0–110.7]). Talazoparib had an overall safety profile consistent with that observed in prior studies in which talazoparib was administered as a single dose. Conclusion Coadministration of itraconazole increased talazoparib plasma exposure compared to talazoparib alone. A reduced talazoparib dose is recommended if coadministration of potent P‐gp inhibitors cannot be avoided. Similar exposure was observed when talazoparib was administered alone and with rifampicin suggesting that the effect of rifampicin on talazoparib exposure is limited.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation of the effect of P‐glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours

Elmeliegy

Làng

Smolyarchuk

et al. 2020

Brit J Clinical Pharma

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“…Despite encouraging response rates and PFS with PARP inhibitors, de‐novo and acquired resistance is a common occurrence. Many potential resistance mechanisms have been proposed; this includes restoration of HRR, up‐regulated signal transduction or by exploiting altered cell cycle regulation . The only mechanism of HRR restoration which has been clinically validated is the development of secondary or ‘reversion’ mutations in BRCA1 or BRCA2.…”

Section: Parp Inhibitor Resistancementioning

confidence: 99%

“…For example, reduction of PARP1 activity with PARP inhibitors leads to activation of the PI3K/AKT prosurvival pathways, providing the rationale for dual PARP and PI3K/AKT pathway inhibition. As HRR is dependent on the phase of the cell cycle, with most HR repair proteins being up‐regulated during G1 to S phase, exploitation of cell cycle regulation by the cancer cell can lead to PARP resistance . Examples of this observed in vitro include up‐regulation of WEE1, which promotes a temporary cell arrest, allowing DNA repair, with increased expression of WEE1 leading to reduced PARP inhibitor sensitivity in vitro.…”

Section: Parp Inhibitor Resistancementioning

confidence: 99%

“…Many potential resistance mechanisms have been proposed; this includes restoration of HRR, up-regulated signal transduction or by exploiting altered cell cycle regulation. 35 The only mechanism of HRR restoration which has been clinically validated is the development of secondary or 'reversion' mutations in BRCA1 or BRCA2. These reversion mutations restore the open reading frame restoring HRR function, thereby leading to PARP inhibitor resistance.…”

Section: Parp Inhibitor Resistancementioning

confidence: 99%

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Targeted therapies in gynaecological cancers

Crusz

Miller

2019

Histopathology

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The treatment of cancer has changed dramatically over the last decade, driven by increased understanding of the cancer genome, immune landscape, molecular alterations and aberrant pathways that drive cancer progression. Advances in molecular biology have led to the development of targeted agents, including monoclonal antibodies, small molecules and check‐point inhibitors. Unlike chemotherapy, which inhibits DNA replication and mitosis, these agents target cancer signalling pathways, stroma, immune microenvironment and vasculature in tumour tissues. In gynaecological cancer, drugs targeting defective DNA repair, such as PARP inhibitors, have been approved for advanced ovarian cancer, and drugs targeting angiogenesis have been used in the treatment of advanced or recurrent ovarian and cervical cancers. Immune check‐point inhibitors such as anti‐PD‐1/PD‐L1 antibodies have proved successful for mismatch repair‐deficient endometrial cancers and HPV‐targeted therapies are under development for HPV‐related malignancies. In this era of precision medicine, improved understanding of cancer biology and genomics needs to be utilised to develop predictive biomarkers for these targeted therapies to maximise patient benefit.

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Cancer Genomics and Evolution

Hendricks¹,

Sekulić²,

Bryce³

et al. 2022

Holland‐Frei Cancer Medicine

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Overview Over 100 years ago, the Nobel Prize for Physiology and Medicine was given to Paul Ehrlich for postulating that “magic bullets” could specifically target and kill cells such as cancer cells based on their unique molecular features. The completed Human Genome Project and the cancer genomics revolution have now mapped many of the genetic changes underlying the unique features of common malignancies. Although cancer has long been recognized to be heterogeneous in its clinical presentation, course, pathology, and response to therapy, we now recognize that it is far more molecularly heterogeneous than anticipated and that such variability will require an individualized approach to patient care. Rather than a single magic bullet, we need an arsenal requiring precise delivery. While inter‐ and intratumoral genomic heterogeneity present significant challenges to cancer management and drug development, a number of developments foster hope for accelerated progress in the war on cancer. First, our catalogue of genomic targets underlying diverse cancers is rapidly growing. Second, we are beginning to understand how diverse mutations converge on a small number of druggable pathways. Third, we continue to develop drugs and biologic agents (e.g., immune checkpoint inhibitors) that target an increasingly diverse array of genomic subtypes of cancer. Finally, advances in “next‐generation” sequencing technologies now enable far earlier detection of disease and disease recurrence. This article focuses on these developments and how their integration is aiding in the precise delivery of “magic bullets.”

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PARP inhibitors: Clinical utility and possibilities of overcoming resistance

Cited by 181 publications

References 68 publications

Evaluation of the effect of P‐glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours

Evaluation of the effect of P‐glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours

Targeted therapies in gynaecological cancers

Cancer Genomics and Evolution

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