PARP Inhibitor

Aka: PARP Inhibitor, Poly ADP Ribose Polymerase Inhibitor, Olaparib, Lynparza, Talazoparib, Telzenna, Niraparib, Zejula, Rucaparib, Rubraca

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II. Indications

  1. Breast Cancer (BRCA mutation, metastatic)
  2. Ovarian Cancer (BRCA mutation, advanced or metastatic)
  3. Prostate Cancer (BRCA mutation)

III. Mechanism

  1. Polyadenosine Diphosphate Ribose Polymerase (PARP)
    1. PARP is a group of enzymes (at least 18) that promote ADP ribose transfer to target Proteins
    2. PARP enzymes are key to DNA/RNA function (structure, transcription, replication, recombination, and repair)
    3. DNA repair includes single strand DNA breaks
  2. PARP Inhibitors
    1. DNA damage is repaired by mechanisms related to both BRCA and PARP
      1. In the absence of these 2 enzyme families, unrepaired DNA defects may lead to cell death
    2. BRCA-related cancer cells survive despite DNA damage due to intact PARP mechanisms
      1. PARP Inhibitors further block DNA repair (in addition to the BRCA mutation)
      2. With both PARP and BRCA non-functional, cancer cells undergo apoptosis and cell death

IV. Medications

  1. Olaparib (Lynparza)
    1. Risk of AML or myelodysplasia, hepatotoxicity, pneumonitis
    2. Adjust dose in moderate hepatic Impairment
    3. Adjust dose with Moderate to Strong CYP3A4 Inhibitors or Inducers
  2. Talazoparib (Telzenna)
    1. Risk of AML or myelodysplasia, myelosuppression
    2. Decrease dose in GFR 30 to 60 ml/min (not studied in GFR <30 ml/min)
    3. May interact with some P-gp Inhibitors and BCRP inhibitors
    4. No hepatic metabolism
  3. Niraparib (Zejula)
    1. Risk of AML or myelodysplasia, myelosuppression and Severe Hypertension (including PRES)
  4. Rucaparib (Rubraca)
    1. Risk of AML or myelodysplasia

V. Dosing

  1. See other references for disease specific dosing protocols

VI. Safety

  1. Avoid in Lactation
    1. Continue to avoid Lactation for at least 1 month after Talazoparib or Niraparib
  2. Avoid in pregnancy (all trimesters, pregnancy category X)
    1. Use reliable Contraception
    2. Continue Contraception for at least 6-7 months after Olaparib, Talazoparib
  3. Monitoring
    1. Complete Blood Count
    2. Liver Function Tests (Olaparib)
    3. Blood Pressure and Heart Rate (Niraparib)

VII. Efficacy

  1. PARP agents (e.g. Olaparib) do not appear to affect survival in BRCA Ovarian Cancer

VIII. Adverse Effects

  1. Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (Olaparib, Talazoparib, Niraparib, Rucaparib)
    1. Rare, but fatal cases have occurred
  2. Myelosuppression with Pancytopenia (Talazoparib, Niraparib)
  3. Interstitial Lung Disease or pneumonitis (Olaparib)
  4. Hepatotoxicity with increased transaminases (Olaparib)
  5. Severe Hypertension or PRES (Niraparib)

IX. Drug Interactions

  1. Moderate to Strong CYP3A4 Inhibitors or Inducers
    1. Avoid or adjust dose of Olaparib
  2. P-gp Inhibitors
    1. Specific P-gp Inhibitors require dose adjustment of Talazoparib
  3. BCRP inhibitors
    1. May interact with Talazoparib

X. Resources

  1. Olaparib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa
  2. Talazoparib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f2423edd-6d24-495c-aec1-c2f457f08d9a
  3. Niraparib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c15c7b7e-4b7f-4489-bbbc-884caeee0669
  4. Rucaparib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a6d46c03-bb1d-417b-b8e5-3bffe352fe29

XI. References

  1. Morales (2014) Crit Rev Eukaryot Gene Expr 24(1):15-28 +PMID: 24579667 [PubMed]

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