Talazoparib

Approved Indications:

• HER2-negative locally advanced or metastatic breast cancer
• Indicated in adult patients with germline BRCA1/2 mutations (gBRCA+) confirmed by an FDA-approved test.
• Advanced or metastatic breast cancer (hormone receptor-positive or triple-negative):
• In patients previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting.

Important Off-label/Clinically Accepted Uses:

• Advanced ovarian cancer with gBRCA mutation (under investigation or compassionate use).
• Prostate cancer (metastatic castration-resistant) with DNA damage repair (DDR) gene mutations including BRCA1/2 (in clinical practice settings).
• Pancreatic adenocarcinoma with gBRCA mutations (investigational settings or guideline-referenced off-label use).

General Adult Dosage (Breast Cancer):

• Recommended dose: 1 mg orally once daily until disease progression or unacceptable toxicity.
• With moderate renal impairment (CrCl 30–59 mL/min): Reduce to 0.75 mg once daily.
• With severe renal impairment (CrCl 15–29 mL/min): Reduce to 0.5 mg once daily.
• Hepatic impairment: No initial dose adjustment required, but monitor for toxicity.

Pediatric Use:

• Not approved for use in pediatric patients.

Elderly Patients:

• No overall differences in safety or efficacy observed, but monitor closely for adverse reactions.

Administration Instructions:

• Swallow capsule whole; do not open, crush, or chew.
• Can be taken with or without food.
• If a dose is missed, take it as soon as possible on the same day. Do not take two doses at the same time.

Talazoparib is an oral poly (ADP-ribose) polymerase (PARP) inhibitor. It inhibits PARP enzymes (primarily PARP1 and PARP2), which are involved in DNA repair through base excision repair. In BRCA1/2-mutated cells, where homologous recombination is already deficient, PARP inhibition leads to accumulation of DNA damage, resulting in synthetic lethality and selective tumor cell death. Talazoparib also traps PARP-DNA complexes, intensifying cytotoxicity beyond enzymatic inhibition alone.

• Absorption:
• Oral bioavailability ~56%.
• Peak plasma concentration (Tmax) occurs ~1–2 hours post-dose.
• Distribution:
• High volume of distribution (Vd ~420 L).
• Plasma protein binding ~74%.
• Metabolism:
• Limited hepatic metabolism; primarily metabolized by non-CYP-mediated pathways.
• Minor involvement of CYP3A4.
• Excretion:
• Elimination half-life ~90 hours.
• Excreted mainly unchanged in feces (68%) and urine (20%).

• Pregnancy:
• Not assigned a formal FDA pregnancy category (under newer labeling rules).
• Embryo-fetal toxicity observed in animal studies.
• Contraindicated in pregnancy. Use effective contraception during treatment and for at least 7 months after the last dose (women) or 4 months (men with female partners).
• Lactation:
• Unknown if excreted in human milk.
• Breastfeeding is not recommended during treatment and for 1 month after the final dose due to potential harm to the infant.

• Primary Class: Antineoplastic Agent
• Subclass: PARP Inhibitor
• Generation: Next-generation potent PARP-DNA trapping agent

• Known hypersensitivity to Talazoparib or any excipients in the formulation.
• Pregnancy due to potential fetal harm.
• Co-administration with certain strong P-glycoprotein (P-gp) inhibitors without dose adjustment.

• Myelosuppression:
• Monitor for anemia, neutropenia, thrombocytopenia; may require dose interruptions or reductions.
• Secondary malignancies (e.g., MDS/AML):
• Reported rarely. Discontinue permanently if confirmed.
• Renal impairment:
• Use with caution in moderate to severe impairment. Monitor renal function periodically.
• Embryo-fetal toxicity:
• Highly teratogenic; pregnancy must be avoided.
• Drug interactions:
• Reduce Talazoparib dose when co-administered with P-gp inhibitors.

Common (≥10%):

• Hematologic:
• Anemia, neutropenia, thrombocytopenia
• Gastrointestinal:
• Nausea, vomiting, decreased appetite, diarrhea, constipation
• General:
• Fatigue, headache, dizziness

Serious/Rare:

• Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
• Severe anemia or thrombocytopenia requiring transfusion
• Hypersensitivity reactions (rare)
• Pulmonary embolism (rare)

• P-glycoprotein (P-gp) inhibitors (e.g., amiodarone, verapamil, clarithromycin):
• May increase Talazoparib plasma concentrations. Dose adjustment required.
• CYP3A4 interactions:
• Minor role in metabolism; avoid strong inducers (e.g., rifampin) when possible.
• No significant food interactions.
• Alcohol:
• No direct interaction known, but alcohol may worsen fatigue or nausea.

• FDA label update (2023–2024):
• Emphasis on use in metastatic breast cancer with gBRCA+ mutation only after genetic testing confirmation.
• Addition of warnings for increased incidence of anemia-related transfusion.
• NCCN Breast Cancer Guidelines:
• Talazoparib included as a category 1 recommendation for patients with germline BRCA mutations and HER2-negative disease.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C.
• Humidity & Light: Store in original container; protect from moisture and light.
• Handling Precautions: Do not open or crush capsules. Use gloves when handling if the capsule is damaged.
• Refrigeration: Not required.