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Talazoparib: Mechanism of Action, Adverse Effects, and Contraindications

Mechanism of Action of PARP Inhibitors:

The poly(ADP-ribose) polymerase (PARP) enzyme participates in cellular DNA repair. Another mechanism for DNA repair is homologous recombination repair (HRR); well-known HRR genes include BRCA1 and BRCA2. Inhibition of PARP with Talazoparib prevents DNA repair. Tumor cells, which divide frequently and exhibit high DNA turnover, are particularly susceptible to damage and undergo apoptosis. Talazoparib is especially effective when HRR is also compromised by mutations.

Indications for Talazoparib plus Enzalutamide

Since 2024 in Europe, talazoparib in combination with enzalutamide has been approved for first-line therapy in patients with metastatic castration-resistant prostate cancer (mCRPC, M1 CRPC) when chemotherapy with docetaxel is not clinically indicated. Demonstration of a BRCA mutation is not mandatory for treatment with talazoparib in Europe. In the United States, talazoparib is approved only for tumors with BRCA mutations.

The TALAPRO-2 trial (Agarwal et al., 2023) showed a prolongation of radiographic progression-free survival in patients with CRPC (HR 0.63). An overall survival analysis is not yet available. In subgroup analyses, the benefit was modest in patients without BRCA mutations (HR 0.70) and pronounced in patients with BRCA mutations (HR 0.20).

Pharmacokinetics of Talazoparib

Absorption is independent of food. The drug is excreted largely unchanged by the kidneys. The half-life is approximately 50 hours.

Adverse Effects of Talazoparib

The most common adverse events (all grades) are anemia, fatigue, nausea, neutropenia, and thrombocytopenia. Frequencies of grade 3–4 events are summarized below (very common >10%, common 1–10%, rare <1%).

• Hematologic: anemia (39%); thrombocytopenia (11%) and neutropenia (17%).
• Vascular: thromboembolism (2%).
• Cardiac: hypertension (16%) and common cardiac arrhythmias.
• Gastrointestinal: very common diarrhea, nausea and vomiting; less commonly, stomatitis or abdominal pain.
• Dermatologic: common alopecia.
• Other: fatigue (5%), dizziness, or headache.

Drug Interactions

Concomitant use of strong P-gp inhibitors (including amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, and verapamil) should be avoided, or the talazoparib dose should be reduced.

Contraindications to Talazoparib

• Hypersensitivity
• Pediatric patients
• Severe hepatic impairment (Child-Pugh C)
• Severe renal impairment (eGFR <15 mL/min)
• Persistent grade 3/4 adverse events despite dose reduction

Dosage of Talazoparib

The recommended dose is 0.5 mg talazoparib once daily in combination with 160 mg enzalutamide once daily. A dose reduction of talazoparib is required in renal impairment: 0.35 mg for eGFR 30–60 ml/min and 0.25 mg for eGFR 15–30 ml/min.

For grade 2 adverse events, interrupt therapy; after improvement, re-challenge at a reduced dose with weekly laboratory monitoring: 0.35 mg as the first reduction, 0.25 mg as the second, and 0.1 mg as the third. Discontinue permanently for recurrent grade 3 or higher toxicity.

Monitoring During Therapy

Obtain a complete blood count with differential monthly. Periodically assess electrolytes, creatinine, skin, and oral mucosa.

Brand Names

Talzenna

References

N. Agarwal et al., “Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial.,” Lancet, vol. 402, no. 10398, pp. 291–303, 2023, doi: 10.1016/S0140-6736(23)01055-3.

  Deutsche Version: Mechanismus, Nebenwirkungen, Kontraindikationen und Dosierung von Talazoparib

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