Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Martorana, Federica; Silva, Leandro Apolinario Da; Sessa, Cristiana; Colombo, Ilaria

doi:10.3390/cancers14040953

Cited by 24 publications

(19 citation statements)

References 142 publications

(325 reference statements)

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“… 48 , 49 While there were no instances of pneumonitis recorded in the TRITON2 study, studies have shown that PARP inhibitors (for example, Olaparib) lead to a significantly increased risk of this and other respiratory toxicities. 28 , 50 Finally, while no patients reported myelodysplastic syndrome (as seen in some trials with rucaparib), one patient died due to acute myeloid leukemia after discontinuing Olaparib (an event also recorded with rucaparib trials). One patient also developed a glioma during the study.…”

Section: Comparison With Other Parp Inhibitorsmentioning

confidence: 99%

Role of Rucaparib in the Treatment of Prostate Cancer: Clinical Perspectives and Considerations

Wu¹,

Goldberg²

2022

CMAR

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Prostate cancer is one of the most common types of cancer worldwide and has strong genetic associations. This is important for the development of therapeutics for the condition, as metastatic castrate-resistant prostate cancer (mCRPC) is resistant to standard androgen deprivation therapy (ADT) and has a relatively poor prognosis. We conducted a literature review on rucaparib, a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor that is currently indicated for the treatment of patients with mCRPC who harbor mutations in BRCA1/2 (homologous recombination repair [HRR] genes) and who have already tried androgen receptor-axis-targeted therapies (ARAT) and a taxane chemotherapy. We describe rucaparib’s FDA approval, which was based on the results of the single-arm, open-label, Phase II TRITON2 clinical trial, which found an objective response rate (ORR) of 43.5%, a duration of response (DOR) of over six months in length and an acceptable safety profile. Rucaparib’s dosage and clinical considerations for use were also discussed. We also compared rucaparib’s use and safety profile with Olaparib, niraparib and talazoparib, three other PARP inhibitors tested for the treatment of mCRPC. Overall, initial results show that the safety profile of all four drugs in mCRPC was relatively similar, and further testing is currently indicated for all four. Differences in their metabolism, however, also warrant further research. The clinical validity of rucaparib will be tested by the follow-up TRITON3 clinical trial, which is comparing the effect of rucaparib compared to standard therapies for mCRPC harboring BRCA1/2 or ATM mutations. Other than TRITON3, other clinical trials are testing rucaparib’s ability against other cancers (prostate or otherwise) with HRR mutations, and also the efficacy of combination therapies involving rucaparib. Finally, more research is needed to elucidate rucaparib’s effect on HRR mutations other than BRCA1/2. Advancements in understanding the genetic landscape of mCRPC will also assist in understanding rucaparib’s full therapeutic potential.

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Section: Comparison With Other Parp Inhibitorsmentioning

confidence: 99%

Role of Rucaparib in the Treatment of Prostate Cancer: Clinical Perspectives and Considerations

Wu¹,

Goldberg²

2022

CMAR

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“…As mentioned, PARPis were demonstrated to be clinically effective, with acceptable tolerability and safety, in a specific range of solid tumors, which led to FDA and European Medicines Agency (EMA) approval of Olaparib, Rucaparib, Niraparib, and Talazoparib [ 31 , 290 ]. However, a consolidated body of evidence from studies of PARPi in patients has identified several adverse events and specific indications for their prevention, monitoring, and management [ 291 , 292 , 293 , 294 ]. PARPi display several on- and off-target toxicities, with hematological and gastrointestinal toxicities among the most common adverse events.…”

Section: Liabilities Upon Treatment With Ddr Inhibitorsmentioning

confidence: 99%

“…PARPi display several on- and off-target toxicities, with hematological and gastrointestinal toxicities among the most common adverse events. Pneumonitis and therapy-related myeloid neoplasias (t-MN), such as AML and myelodysplastic syndromes (MDS), have been reported with PARPi, but despite their rare frequency, they are potentially life-threatening, often fatal, and deserve particular attention due to their severity [ 291 ]. The t-MN is typically a late complication of some chemo- and radiotherapy, and the subtype and latency period are usually treatment-dependent [ 295 ].…”

Section: Liabilities Upon Treatment With Ddr Inhibitorsmentioning

confidence: 99%

DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities

Jurkovičová

Neophytou²,

Gašparović³

et al. 2022

IJMS

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Resistance to chemo- and radiotherapy is a common event among cancer patients and a reason why new cancer therapies and therapeutic strategies need to be in continuous investigation and development. DNA damage response (DDR) comprises several pathways that eliminate DNA damage to maintain genomic stability and integrity, but different types of cancers are associated with DDR machinery defects. Many improvements have been made in recent years, providing several drugs and therapeutic strategies for cancer patients, including those targeting the DDR pathways. Currently, poly (ADP-ribose) polymerase inhibitors (PARP inhibitors) are the DDR inhibitors (DDRi) approved for several cancers, including breast, ovarian, pancreatic, and prostate cancer. However, PARPi resistance is a growing issue in clinical settings that increases disease relapse and aggravate patients’ prognosis. Additionally, resistance to other DDRi is also being found and investigated. The resistance mechanisms to DDRi include reversion mutations, epigenetic modification, stabilization of the replication fork, and increased drug efflux. This review highlights the DDR pathways in cancer therapy, its role in the resistance to conventional treatments, and its exploitation for anticancer treatment. Biomarkers of treatment response, combination strategies with other anticancer agents, resistance mechanisms, and liabilities of treatment with DDR inhibitors are also discussed.

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“…Theoretically, such combinations should improve fractional cell kill and, by extension, clinical effectiveness. However, impairing DNA repair in other rapidly proliferating tissues, such as bone marrow and gastrointestinal mucosa, will result in increased toxicity to these cells and potential life-threatening complications, limiting the utility of such combinatorial therapeutic approaches [40,41]. This is evidenced clinically in trials of MGMT inhibitors and more recently, PARP inhibitors (PARPi) and other DNA repair inhibitors, in combinations with chemotherapy [41][42][43].…”

Section: Dna Repair and Cancermentioning

confidence: 99%

Evolving DNA repair synthetic lethality targets in cancer

et al. 2022

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DNA damage signaling response and repair (DDR) is a critical defense mechanism against genomic instability. Impaired DNA repair capacity is an important risk factor for cancer development. On the other hand, upregulation of DDR mechanisms is a feature of cancer chemotherapy and radiotherapy resistance. Advances in our understanding of DDR and its complex role in cancer has led to several translational DNA repair targeted investigations culminating in clinically viable precision oncology strategy using PARP inhibitors in breast, ovarian, pancreatic and prostate cancers. Whilst PARP directed synthetic lethality has improved outcomes for many patients, the lack of sustained clinical response and the development of resistance pose significant clinical challenges. Therefore, the search for additional DDR directed drug targets and novel synthetic lethality approaches is highly desirable and is an area of intense pre-clinical and clinical investigation. Here we provide an overview of the mammalian DNA repair pathways and then focus on current state of PARP inhibitors and other emerging DNA repair inhibitors for synthetic lethality in cancer.

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Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Cited by 24 publications

References 142 publications

Role of Rucaparib in the Treatment of Prostate Cancer: Clinical Perspectives and Considerations

Role of Rucaparib in the Treatment of Prostate Cancer: Clinical Perspectives and Considerations

DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities

Evolving DNA repair synthetic lethality targets in cancer

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