Management of Adverse Events During Rucaparib Treatment for Relapsed Ovarian Cancer: A Review of Published Studies and Practical Guidance

Lorusso, Domenica; García-Donás, Jesús; Sehouli, Jalid; Joly, Florence

doi:10.1007/s11523-020-00715-z

Cited by 14 publications

(9 citation statements)

References 55 publications

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“…For example, rash has been associated with improved survival outcomes for many anticancer medicines, including chemotherapies [29][30][31]. However, diarrhoea and improved outcomes may be afatinib specific; for example, diarrhoea has been associated with worsened survival outcomes for other anticancer treatment options [13,[32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Survival Outcomes of Nonsmall Cell Lung Cancer Patients Treated with Afatinib Who Are Affected by Early Adverse Events

Logan

Brooks

Rowland

et al. 2021

Journal of Oncology

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Introduction. Afatinib is a first-line treatment option for patients with an advanced nonsmall cell lung cancer (NSCLC) expressing an epidermal growth factor receptor (EGFR) activating mutation. This study aimed to evaluate the association between early adverse events induced by afatinib and overall survival (OS) and progression free survival (PFS) in patients with advanced NSCLC. Methods. The study was a pooled post hoc analysis of the randomized trials LUX-Lung 3 and LUX-Lung 6 which evaluated afatinib versus pemetrexed-cisplatin or gemcitabine-cisplatin, respectively. Cox proportional hazard analysis was used to assess the impact of adverse events occurring within the first 28 days of afatinib therapy on the PFS and OS outcomes in treatment-naïve advanced NSCLC patients harbouring an EGFR activating mutation. Results. There were 468 patients who initiated first-line afatinib therapy within LUX-Lung 3 and LUX-Lung 6. A significant association between early rash and improved OS (hazard ratio (HR 95% CI); grade 1 = 0.74 [0.56–0.97]; grade 2+ = 0.64 [0.46–0.89]) ( P = 0.018) was observed, although no significant association with PFS was present ( P = 0.732). A significant association was identified between early diarrhoea and improved PFS (grade 1 = 0.83 [0.62–1.12]; grade 2+ = 0.62 [0.44–0.88]) ( P = 0. 015), although no significant association with OS was present ( P = 0.605). No associations between early stomatitis or paronychia and OS or PFS were identified. Conclusion. Rash occurring early after the initiation of afatinib was significantly associated with improved OS, an indicator that rash may be a surrogate of patients likely to achieve long-term survival. Consideration of using rash as a dose adjustment target may be warranted for future prospective trials aiming to optimise outcomes with afatinib therapy.

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Section: Discussionmentioning

confidence: 99%

Survival Outcomes of Nonsmall Cell Lung Cancer Patients Treated with Afatinib Who Are Affected by Early Adverse Events

Logan

Brooks

Rowland

et al. 2021

Journal of Oncology

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“…In these cases, rucaparib should be withheld until ALT/AST levels return to G ≤ 2. Dose reduction can be considered for G3 transaminitis, while this is mandatory in cases of G4 events [ 73 ].…”

Section: Safety Profile Of Ddr-targeting Agentsmentioning

confidence: 99%

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

Martorana

Silva

Sessa

et al. 2022

Cancers

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Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors of other key components of DNA repair, such as ATR, CHK1 and WEE1, have been developed and are currently under investigation in clinical trials. The inhibition of DDR inevitably induces on-target and off-target adverse events. Hematological and gastrointestinal toxicities as well as fatigue are common with all DDR-targeting agents, while other adverse events are drug specific, such as hypertension with niraparib and transaminase elevation with rucaparib. Cases of pneumonitis and secondary hematological malignancies have been reported with PARP inhibitors and, despite being overly rare, they deserve particular attention due to their severity. Safety also represents a crucial issue for the development of combination regimens incorporating DDR-targeting agents with other treatments, such as chemotherapy, anti-angiogenics or immunotherapy. As such, overlapping and cumulative toxicities should be considered, especially when more than two classes of drugs are combined. Here, we review the safety profile of DDR-targeting agents when used as single agents or in combination and we provide principles of toxicity management.

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“…44 1.3% of patients who had a long-term safety follow-up also reported these diagnoses. 42 , 44 It was noted, however, that these diagnoses were not necessarily due to rucaparib, as all patients assessed had previously undergone treatment with platinum-containing chemotherapy treatments and other DNA damaging agents. 44 Interestingly, during the course of the TRITON2 clinical trial no reports of myelodysplastic syndrome or acute myeloid lymphoma were recorded, perhaps suggesting better outcomes.…”

Section: Current Uses Of Rucaparibmentioning

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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Management of Adverse Events During Rucaparib Treatment for Relapsed Ovarian Cancer: A Review of Published Studies and Practical Guidance

Cited by 14 publications

References 55 publications

Survival Outcomes of Nonsmall Cell Lung Cancer Patients Treated with Afatinib Who Are Affected by Early Adverse Events

Survival Outcomes of Nonsmall Cell Lung Cancer Patients Treated with Afatinib Who Are Affected by Early Adverse Events

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

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

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