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

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Related Studies

Ontology: Poly(ADP-ribose) polymerase inhibitor (C1882413)

Definition (NCI_NCI-GLOSS) A substance that blocks an enzyme involved in many functions of the cell, including the repair of DNA damage. DNA damage may be caused by normal cell actions, UV light, some anticancer drugs, and radiation used to treat cancer. It may cause cancer cells to die. It is a type of targeted therapy.
Definition (NCI) Any substance that inhibits Poly (ADP-Ribose) polymerase, an enzyme involved in detecting DNA single strand breaks and the initiation of DNA repair. Inhibition of Poly (ADP-Ribose) polymerase has direct cytotoxic effects by inhibiting DNA repair and causing cell death.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
SnomedCT 432253008, 432251005
English Poly (ADP-Ribose) Polymerase Inhibitor, PARP Inhibitor, Nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor (substance), Poly(ADP-ribose) polymerase inhibitor, Nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor, Nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor (product), poly (ADP-ribose) polymerase inhibitor, PARP inhibitor
Spanish inhibidor de nicotinamida adenina dinucleótido ribosiltransferasa de difosfato de adenosina, inhibidor de nicotinamida adenina dinucleótido ribosiltransferasa de difosfato de adenosina (sustancia), inhibidor de nicotinamida adenina dinucleótido adenosina difosfato ribosiltransferasa, inhibidor de poli-(ADP-ribosa) polimerasa, inhibidor de poli(ADP-ribosa) polimerasa, inhibidor de nicotinamida adenina dinucleótido adenosina difosfato ribosiltransferasa (producto)

Ontology: Olaparib (C2316164)

Definition (NCI) A small molecule inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential chemosensitizing, radiosensitizing, and antineoplastic activities. Olaparib selectively binds to and inhibits PARP, inhibiting PARP-mediated repair of single strand DNA breaks; PARP inhibition may enhance the cytotoxicity of DNA-damaging agents and may reverse tumor cell chemoresistance and radioresistance. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins and can be activated by single-stranded DNA breaks.
Definition (NCI_NCI-GLOSS) A substance being studied in the treatment of breast, ovarian, and prostate cancers caused by mutations (changes) in the BRCA1 and BRCA2 genes. It is also being studied in the treatment of other types of cancer. It blocks an enzyme involved in many functions of the cell, including the repair of DNA damage. DNA damage may be caused by normal cell actions, UV light, some anticancer drugs, and radiation used to treat cancer. AZD2281 may cause cancer cells to die. It is a type of targeted therapy agent and a type of poly (ADP-ribose) polymerase inhibitor.
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
SnomedCT 432162002, 432885003
English Olaparib (substance), Olaparib, Olaparib (product), PARP Inhibitor AZD2281, olaparib, OLAPARIB, PARP inhibitor AZD2281
Spanish olaparib, olaparib (sustancia), olaparib (producto)

Ontology: 2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (C2744440)

Concepts Organic Chemical (T109)
MSH C545685
English 2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide

Ontology: Rucaparib Phosphate (C3642418)

Definition (NCI_NCI-GLOSS) A substance being studied in the treatment of breast cancers caused by mutations (changes) in the BRCA1 and BRCA2 genes. It is also being studied in the treatment of other types of cancer. It blocks an enzyme involved in many functions of the cell, including the repair of DNA damage. DNA damage may be caused by normal cell actions, UV light, some anticancer drugs, and radiation used to treat cancer. AG014699 may cause cancer cells to die. It is a type of poly(ADP-ribose) polymerase inhibitor.
Definition (NCI) A tricyclic indole poly(ADP-Ribose) polymerase (PARP1) inhibitor with potential chemosensitizing, radiosensitizing, and antineoplastic activities. Rucaparib selectively binds to PARP1 and inhibits PARP1-mediated DNA repair, thereby enhancing the accumulation of DNA strand breaks and promoting genomic instability and apoptosis. This may enhance the cytotoxicity of DNA-damaging agents and reverse tumor cell resistance to chemotherapy and radiation therapy. PARP1 catalyzes post-translational ADP-ribosylation of nuclear proteins and is activated by single-strand DNA (ssDNA) breaks.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
English Rucaparib Phosphate, RUCAPARIB PHOSPHATE