Discrepancy in calculated and measured glomerular filtration rates in patients treated with PARP inhibitors

Molin, Graziela Zibetti Dal; Westin, Shannon N.; Msaouel, Pavlos; Gomes, L.; Dickens, Andrea S.; Coleman, Robert L.

doi:10.1136/ijgc-2019-000714

Cited by 36 publications

(29 citation statements)

References 19 publications

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“…Our observations are in line with a recently published study on the discrepancy between the calculated GFR using creatinine and the measured GFR using GFR scans in patients using PARP inhibitors, which empowers our hypothesis. In this study, a significant decline in creatinine-derived eGFR was found, while the eGFR from renal scans was nearly identical [19]. Here, we confirm these results with an additional and easily accessible biomarker for renal clearance and show the dose dependency of this effect.…”

Section: Effect Of Olaparib On Creatinine Cystatin C and Egfrsupporting

confidence: 85%

A real or apparent decrease in glomerular filtration rate in patients using olaparib?

Bruin

Korse

Wijnen

et al. 2020

Eur J Clin Pharmacol

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Purpose Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for ovarian and metastatic breast cancer. Increased serum creatinine levels have been observed in patients taking olaparib, but the underlying mechanism is unknown. This study aimed to investigate if patients receiving olaparib have increased creatinine levels during olaparib treatment and whether this actually relates to a declined glomerular filtration rate (GFR). Methods We retrospectively identified patients using olaparib at the Netherlands Cancer Institute – Antoni van Leeuwenhoek (NKI-AVL) from 2012 until 2020. Patients with at least one plasma or serum sample available at baseline/off treatment and during olaparib treatment were included. Cystatin C levels were measured, creatinine levels were available and renal function was determined by calculating the estimated glomerular filtration rate (eGFR) using the Creatinine Equation (CKD-EPI 2009) and the Cystatin C Equation (CKD-EPI 2012). Results In total, 66 patients were included. Olaparib treatment was associated with a 14% increase in median creatinine from 72 (inter quartile range (IQR): 22) μmol/L before/off treatment to 82 (IQR: 20) μmol/L during treatment (p < 0.001) and a 13% decrease in median creatinine-derived eGFR from 86 (IQR: 26) mL/min/1.73 m2 before/off treatment to 75 (IQR: 29) mL/min/1.73 m2 during treatment (p < 0.001). Olaparib treatment had no significant effect on median cystatin C levels (p = 0.520) and the median cystatin C–derived eGFR (p = 0.918). Conclusions This study demonstrates that olaparib likely causes inhibition of renal transporters leading to a reversible and dose-dependent increase in creatinine and does not affect GFR, since the median cystatin C–derived eGFR was comparable before/off treatment and during treatment of olaparib. Using the creatinine-derived eGFR can give an underestimation of GFR in patients taking olaparib. Therefore, an alternative renal marker such as cystatin C should be used to accurately calculate eGFR in patients taking olaparib.

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Section: Effect Of Olaparib On Creatinine Cystatin C and Egfrsupporting

confidence: 85%

A real or apparent decrease in glomerular filtration rate in patients using olaparib?

Bruin

Korse

Wijnen

et al. 2020

Eur J Clin Pharmacol

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“…In the same analysis, median (95% CI) time to onset of anygrade thrombocytopenia/decreased platelet count was 52 (43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57) days, and median (95% CI) time to onset of grade 3 or higher thrombocytopenia/decreased platelet count was 47 (29-63) days [21]. Any-grade neutropenia/decreased neutrophil count was reported in 16.2% of patients in the integrated analysis of safety (median [95% CI] time to onset, 67 In our experience, short-term interruptions in combination with iron and folate supplements are helpful for patients with grade 2 anemia/decreased hemoglobin.…”

Section: Anemia Thrombocytopenia or Neutropeniamentioning

confidence: 83%

“…obstruction, dehydration, concomitant medication) should be excluded through appropriate assessments. Alternative methods for assessing renal function may be needed as discordance between estimated glomerular filtration rate (GFR) based on serum creatinine levels and calculated GFR obtained through a nuclear medicine scan was commonly observed (63% of matched assessments) in a retrospective study of patients who received PARP inhibitors [53]. If true renal dysfunction is confirmed, dose reduction may be required once creatinine levels have Hematologic AEs Blood count testing should be completed prior to starting treatment, and monthly thereafter improved.…”

Section: Increased Blood Creatininementioning

confidence: 99%

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

et al. 2020

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The poly(ADP-ribose) polymerase inhibitor rucaparib is approved as monotherapy in the treatment and maintenance settings for women with relapsed ovarian cancer in the European Union and the United States. We review the safety profile of rucaparib in both settings and provide recommendations for the clinical management of the main adverse events (AEs) that may occur during rucaparib treatment. We searched PubMed and congress proceedings for safety data on oral rucaparib monotherapy (600 mg twice daily) from clinical trials involving patients with relapsed ovarian cancer. AE management guidance was developed from clinical trial protocols, rucaparib prescribing information, oncology association guidelines, and author experience. The most frequent any-grade treatment-emergent AEs (TEAEs) included gastrointestinal symptoms, asthenia/fatigue, dysgeusia, anemia/decreased hemoglobin, and increased alanine/aspartate aminotransferase. Across clinical trials, 61.8% of patients had one or more grade 3 or higher TEAEs. Clinicians should employ close follow-up for TEAEs, particularly early in treatment, and educate patients about expected TEAEs and methods for their monitoring and management (e.g., antiemetics for nausea/vomiting, transfusions for hematologic TEAEs, or dose interruptions/reductions for moderate/severe TEAEs). Overall, 16.2% of patients discontinued rucaparib due to TEAEs. Management of AEs that may occur during rucaparib treatment is crucial for patients to obtain optimal clinical benefit by remaining on therapy and to avoid their detrimental impact on quality of life. Jalid Sehouli and Florence Joly contributed equally to this work.

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“…Elevated creatinine has been observed with multiple PARP inhibitors and is thought to be due to inhibition of renal transporters (eg, MATE-1, MATE2-K, OCT2) rather than a direct impact on renal function. 19 , 32 - 35 Although there have been reports of fatal pneumonitis with other PARP inhibitors, 34 interstitial lung disease has not been identified as a potential risk from rucaparib treatment when evaluated across studies in multiple tumor types; the majority of cases had an alternative etiology, and most resolved with continued rucaparib treatment or after dose interruption with negative rechallenge.…”

Section: Discussionmentioning

confidence: 99%

Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring aBRCA1orBRCA2Gene Alteration

Abida

Patnaik

Campbell

et al. 2020

JCO

547

484

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PURPOSE BRCA1 or BRCA2 ( BRCA) alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from patients with mCRPC associated with a BRCA alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study. METHODS We enrolled patients who progressed after one to two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy for mCRPC. Efficacy and safety populations included patients with a deleterious BRCA alteration who received ≥ 1 dose of rucaparib. Key efficacy end points were objective response rate (ORR; per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators) and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate. RESULTS Efficacy and safety populations included 115 patients with a BRCA alteration with or without measurable disease. Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients), respectively. The confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration, while a higher PSA response rate was observed in patients with a BRCA2 alteration. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (25.2%; 29 of 115 patients). CONCLUSION Rucaparib has antitumor activity in patients with mCRPC and a deleterious BRCA alteration, but with a manageable safety profile consistent with that reported in other solid tumor types.

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Discrepancy in calculated and measured glomerular filtration rates in patients treated with PARP inhibitors

Cited by 36 publications

References 19 publications

A real or apparent decrease in glomerular filtration rate in patients using olaparib?

A real or apparent decrease in glomerular filtration rate in patients using olaparib?

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

Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring aBRCA1orBRCA2Gene Alteration

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