TALZENNA 0.25MG ​ ​CAPSULE

Indications

• Breast cancer with germline BRCA mutations
• Targeted therapy responsive malignancy including certain types of ovarian cancer

Mechanism of action

Talazoparib inhibits poly(ADP-ribose) polymerases (PARPs), enzymes that are essential for DNA repair. By blocking the base excision repair (BER) pathway, talazoparib leads to the accumulation of unrepaired single-strand breaks (SSBs), resulting in double-strand breaks (DSBs), which are particularly harmful to cells lacking functional BRCA1 or BRCA2. The inhibition of PARP in these cancer cells creates a state of 'synthetic lethality', causing increased DNA damage and promoting apoptosis.

Pharmacodynamics

Talazoparib demonstrates significant cytotoxic effects against cancer cell lines with defects in DNA repair, including those with mutations in BRCA1 and BRCA2. Its anti-tumour efficacy has been observed in models of breast cancer, where it effectively induces cell death in cells that are unable to repair DNA damage adequately. This action is primarily due to talazoparib's ability to interfere with the normal DNA repair processes, leading to enhanced tumour cell death.

Pharmacokinetics

Talazoparib is administered orally and has a bioavailability that allows for effective systemic exposure. It is metabolized primarily by the liver, and its pharmacokinetic profile may be influenced by factors such as hepatic function and concomitant medications. The drug is typically dosed once daily, and adjustments may be necessary based on side effects or interactions with other drugs. Detailed pharmacokinetic parameters, including half-life and clearance rates, should be referred to in specific product literature.

Adverse effects

• Anaemia
• Decreased appetite
• Headache
• Nausea
• Vomiting
• Fatigue
• Myalgia
• Pain
• Peripheral oedema
• Rash
• Increased risk of infection
• Gastrointestinal discomfort
• Dizziness
• Hepatic disorders
• Hypertension

Interactions

• berotralstat+talazoparib: Moderate (increases concentration)
• sotorasib+talazoparib: Moderate (increases exposure)
• tucatinib+talazoparib: Moderate (increases exposure)
• propafenone+talazoparib: Unknown (increases exposure)
• verapamil+talazoparib: Unknown (increases exposure)
• ciclosporin+talazoparib: Unknown (increases exposure)
• cobicistat+talazoparib: Unknown (increases exposure)
• eltrombopag+talazoparib: Unknown (increases exposure)
• ibrutinib+talazoparib: Unknown (increases exposure)
• ivacaftor+talazoparib: Unknown (increases exposure)

Precautions

• Avoid in pregnancy unless potential benefit outweighs risk as toxicity observed in animal studies.
• Avoid in breastfeeding; no information available.
• Monitor for side effects and consider dose adjustments if necessary.
• Use effective contraception in women of childbearing potential during treatment and for 7 months post-treatment.
• Male patients should use effective contraception during treatment and for at least 4 months after.

Pregnancy

Avoid unless potential benefit outweighs risk; toxicity in animal studies has been reported.

Breast-feeding

Avoid during treatment and for 1 month after the last dose; no information available.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Talazoparib 1 mg tablets
• Talazoparib 960 mg tablets

Mechanism of action

Poly(ADP-ribose) polymerases (PARPs) are multifunctional enzymes involved in essential cellular functions, such as DNA transcription and DNA repair. PARPs recognize and repair DNA single-strand breaks (SSBs) via the base excision repair (BER) pathway. DNA double-strand breaks (DSBs) are repaired via homologous recombination by tumour suppressor proteins encoded by _BRCA1_ and _BRCA2_. Talazoparib is a potent inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1 and PARP2. _In vitro_, talazoparib binds to PARP-1 and -2 isoforms with similar affinity. Inhibition of the BER pathway by talazoparib leads to the accumulation of unrepaired SSBs, which leads to the formation of DSBs, which is the most toxic form of DNA damage. While BRCA-dependent homologous recombination can repair DSBs in normal cells, this repair pathway is defective in cells with BRCA1/2 mutations, such as certain tumour cells. Inhibition of PARP in cancer cells with BRCA mutations leads to genomic instability and apoptotic cell death. This end result is also referred to as synthetic lethality, a phenomenon where the combination of two defects - inhibition of PARP activity and loss of DSB repair by HR - that are otherwise benign when alone leads to detrimental results. By inhibiting PARP, talazoparib increases the formation of PARP-DNA complexes resulting in DNA damage, decreased cell proliferation, and apoptosis.

Pharmacodynamics

Talazoparib is a cytotoxic and anti-tumour agent. _In vitro_, talazoparib caused cytotoxicity in cancer cell lines that harboured defects in DNA repair genes, including BRCA1 and BRCA2. Talazoparib mediated anti-tumour effects on patient-derived xenograft breast cancer models bearing mutated BRCA1 or mutated BRCA2 or wild type BRCA1 and BRCA2.