Talazoparib

Talazoparib inhibits the PARP1 and PARP2 enzymes, which take part in the cell’s response to DNA damage. It works in two ways: it blocks the catalytic activity of PARP, and it traps the PARP protein on DNA lesions so that repair, replication and transcription are prevented. Cells with defects in DNA repair genes, such as BRCA1 and BRCA2, are particularly sensitive.

Mechanism of Action

• PARP inhibition: the SmPC reports IC50 values of 0.7 nM for PARP1 and 0.3 nM for PARP2. PARP enzymes are involved in DNA repair, gene transcription and cell-death signalling.
• PARP trapping: PARP bound to talazoparib does not readily detach from the DNA lesion, which blocks DNA repair, replication and transcription and leads to apoptosis or cell death.
• Synthetic lethality: blocking base-excision repair leaves single-strand breaks unrepaired, and these turn into double-strand breaks. Cells with BRCA1/2 mutations cannot repair double-strand breaks by homologous recombination, so damage accumulates and the cells die. In cell lines with DNA repair defects, talazoparib raised γH2AX (a marker of double-strand breaks), reduced proliferation and increased apoptosis.
• With enzalutamide: blocking androgen-receptor signalling suppresses homologous recombination repair genes, including BRCA1, which makes cells sensitive to PARP inhibition. PARP1 activity is also needed for full androgen-receptor function, so PARP inhibition may increase sensitivity to androgen-receptor signalling inhibitors.
• Animal models: anti-tumour activity was seen in a BRCA-mutant breast cancer xenograft derived from a patient previously treated with platinum, and in an androgen-receptor-positive prostate cancer xenograft.

Pharmacokinetics

• Absorption: the median time to peak concentration is 1–2 hours. Absolute bioavailability has not been studied in humans; urinary excretion data indicate at least 41%, with at least 69% absorbed. Exposure rises roughly in proportion to dose between 0.025 and 2 mg. Steady state is reached within 2–3 weeks alone, and in about 9 weeks together with enzalutamide. Food lowers the peak concentration by about 46% and delays it (median 1 to 4 hours) without changing total exposure, so the capsules can be taken with or without food. Acid-reducing agents have no significant effect on absorption.
• Distribution: apparent volume of distribution about 420 L; about 74% bound to plasma proteins in vitro, independent of concentration.
• Metabolism: minimal hepatic metabolism; after a radiolabelled dose, talazoparib was the only circulating drug-derived entity identified. In vitro it did not inhibit or induce the major CYP enzymes or UGT isoforms, nor inhibit the major membrane transporters, at clinically relevant concentrations. It is a substrate of P-gp and BCRP.
• Elimination: renal excretion of unchanged drug (filtration and active secretion, probably involving P-gp) is the main route. Mean terminal half-life about 90 hours (±58); apparent oral clearance about 6.5 L/h. After a radiolabelled dose, about 69% was recovered in urine (55% as unchanged drug) and 20% in faeces (14% unchanged).
• Special populations: age (18–88 years), sex and body weight have no clinically relevant effect. Exposure is about 19% lower in Asian patients. In monotherapy, total exposure rose by 92% in moderate and 169% in severe renal impairment compared with normal renal function, while mild impairment made no clear difference; hepatic impairment (mild, moderate or severe) had no significant effect. Talazoparib has not been studied in children, in patients on haemodialysis, or, with enzalutamide, in hepatic impairment.

• Breast cancer: as monotherapy for adults with germline BRCA1/2 mutations who have HER2-negative locally advanced or metastatic breast cancer. Patients should have been previously treated with an anthracycline and/or a taxane in the (neo)adjuvant, locally advanced or metastatic setting, unless they were not suitable for these treatments. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine-based therapy, or be considered unsuitable for endocrine-based therapy.
• Prostate cancer: in combination with enzalutamide for adults with metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated.

• Hypersensitivity to talazoparib or to any of the excipients.
• Breast-feeding (during treatment and for at least 1 month after the final dose).

The safety profile rests on pooled data from 1,088 patients: 690 who received talazoparib 1 mg as monotherapy in solid-tumour studies and 398 with metastatic castration-resistant prostate cancer who received 0.5 mg with enzalutamide 160 mg (TALAPRO-2). The most common reactions (≥20% of patients) were anaemia (55.6%), fatigue (52.5%), nausea (35.8%), neutropenia (30.3%), thrombocytopenia (25.2%) and decreased appetite (21.1%). The most common grade 3 or higher reactions (≥10%) were anaemia (39.2%), neutropenia (16.5%) and thrombocytopenia (11.1%).

Very common (≥1/10): anaemia, neutropenia, thrombocytopenia, leukopenia, decreased appetite, dizziness, headache, nausea, vomiting, diarrhoea, abdominal pain, alopecia, fatigue (including asthenia).

Common (≥1/100 to <1/10): lymphopenia, dysgeusia, venous thromboembolism (pulmonary embolism, deep vein thrombosis and other venous embolism or thrombosis), stomatitis, dyspepsia.

Uncommon (≥1/1,000 to <1/100): myelodysplastic syndrome/acute myeloid leukaemia.

Myelosuppression is the main reason for dose changes. On monotherapy, dose modifications for any adverse reaction were needed in 58.7% of patients (anaemia 33.5%, neutropenia 11.7%, thrombocytopenia 9.9%) and treatment was permanently stopped in 2.9%. With enzalutamide, doses were interrupted in 62.1% of patients (anaemia 44%), reduced in 52.8% and permanently stopped in 18.8%. Fatal (grade 5) venous thromboembolic events were reported, and myelodysplastic syndrome or acute myeloid leukaemia has been reported in below 1% of solid-tumour patients treated with talazoparib in clinical studies.

Talazoparib is a substrate of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and is eliminated mainly as unchanged drug by the kidneys, so the relevant interactions involve these transporters.

• Strong P-gp inhibitors: itraconazole raised talazoparib total exposure by about 56% and peak concentration by about 40% in a single-dose study, and population analysis showed a 45% rise with strong P-gp inhibitors. The combination should be avoided (the SmPC lists, among others, amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir and verapamil). If it cannot be avoided, the talazoparib dose is reduced (see Administration and Dosage).
• Enzalutamide: enzalutamide 160 mg increases talazoparib exposure about 2-fold, which is why the dose with enzalutamide is 0.5 mg. The effect of other P-gp inhibitors given together with enzalutamide has not been studied; they should be avoided, and if that is not possible the patient should be monitored for increased adverse reactions.
• P-gp inducers: rifampicin did not change total exposure and raised the peak concentration by about 37%, probably the net effect of P-gp induction and inhibition; no dose adjustment is needed with rifampicin. Other P-gp inducers (including carbamazepine, phenytoin and St John’s wort) have not been studied and may lower talazoparib exposure.
• BCRP inhibitors: may raise exposure. Strong BCRP inhibitors (including curcumin and ciclosporin) should be avoided; if that is not possible, monitor for increased adverse reactions.
• Acid-reducing agents: proton pump inhibitors, histamine H2-receptor antagonists and other acid-reducing agents have no significant effect on absorption.
• Hormonal contraception: interaction studies with oral contraceptives have not been done, and hormonal contraception is not recommended in patients with breast cancer (see Special Instructions).
• Food: a high-fat, high-calorie meal lowers the peak concentration but not total exposure; talazoparib can be taken with or without food.

Treatment should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. The capsules are swallowed whole, with or without food. They must not be opened or dissolved, to avoid contact with the capsule content.

Patient Selection

• Breast cancer: patients are selected on the presence of deleterious or suspected deleterious germline BRCA mutations, determined by an experienced laboratory with a validated test. Genetic counselling is offered according to local regulations, as applicable.
• Prostate cancer: tumour mutation testing is not required.

Recommended Dose

• Breast cancer (monotherapy): 1 mg once daily until disease progression or unacceptable toxicity.
• Prostate cancer (with enzalutamide): 0.5 mg talazoparib with 160 mg enzalutamide, both once daily, until disease progression or unacceptable toxicity. Medical castration with a luteinising hormone-releasing hormone (LHRH) analogue continues in patients who are not surgically castrated. The enzalutamide product information gives its own dosing.

Dose Adjustments for Side Effects

• A complete blood count is obtained before starting and monitored monthly and as clinically indicated.
• Haematological reactions: withhold talazoparib if haemoglobin falls below 8 g/dL, platelets below 50,000/µL or neutrophils below 1,000/µL. Resume at the next lower dose once levels recover to ≥9 g/dL, ≥75,000/µL and ≥1,500/µL respectively.
• Non-haematological reactions of grade 3 or 4: withhold until grade 1 or less, then consider resuming at the next lower dose or discontinuing.
• Dose levels for breast cancer: 1 mg, then 0.75 mg, 0.5 mg and 0.25 mg once daily at the first, second and third reductions.
• Dose levels with enzalutamide: 0.5 mg, then 0.35 mg, 0.25 mg and 0.1 mg once daily at the first, second and third reductions. The 0.1 mg capsule is intended to support dose modifications and is not interchangeable with other strengths.
• Strong P-gp inhibitors: in breast cancer, avoid them; if unavoidable, reduce to the next lower dose and return to the previous dose after 3–5 half-lives of the inhibitor once it is stopped. With enzalutamide, P-gp inhibitors should be avoided.

Special Populations

• Hepatic impairment: no dose adjustment for mild, moderate or severe impairment (defined by bilirubin and AST). With enzalutamide, use in severe hepatic impairment (Child-Pugh C) is not recommended because pharmacokinetics and safety have not been established.
• Renal impairment, breast cancer: no adjustment for mild impairment; starting dose 0.75 mg once daily for moderate impairment (creatinine clearance 30 to below 60 mL/min) and 0.5 mg once daily for severe impairment (15 to below 30 mL/min).
• Renal impairment, prostate cancer: no adjustment for mild impairment; 0.35 mg once daily with enzalutamide for moderate impairment and 0.25 mg once daily with enzalutamide for severe impairment. Talazoparib has not been studied below 15 mL/min or in patients needing haemodialysis.
• Elderly: no dose adjustment (65 years and over).
• Children and adolescents: safety and efficacy below 18 years have not been established.

Missed or Vomited Dose

Do not take an additional dose. Take the next prescribed dose at the usual time.

Myelosuppression

Anaemia, leukopenia/neutropenia and thrombocytopenia have been reported. Talazoparib should not be started until the patient has recovered from haematological toxicity of previous therapy (grade 1 or less). Haematology parameters and the signs and symptoms of anaemia, leukopenia/neutropenia and thrombocytopenia are monitored routinely, and dose reduction or interruption is recommended if these occur. Supportive care, with or without transfusions and/or colony-stimulating factors, may be used as appropriate.

Myelodysplastic Syndrome and Acute Myeloid Leukaemia

These conditions have been reported with PARP inhibitors, including talazoparib (below 1% of solid-tumour patients in clinical studies). Possible contributing factors include previous platinum-containing chemotherapy, other DNA-damaging agents and radiotherapy. Blood counts are monitored monthly; if the diagnosis is confirmed, talazoparib is discontinued.

Venous Thromboembolic Events

In metastatic castration-resistant prostate cancer, venous thromboembolic events were more frequent with talazoparib plus enzalutamide than with enzalutamide alone. Patients should be monitored for signs and symptoms of deep vein thrombosis and pulmonary embolism and treated as medically appropriate.

Pregnancy, Contraception, Breastfeeding and Fertility

• Pregnancy test: talazoparib was clastogenic in an in vitro chromosomal aberration assay and an in vivo rat bone marrow micronucleus assay, but not mutagenic in the Ames assay, and may cause foetal harm. A pregnancy test is performed in all women of childbearing potential before treatment, and they should not be pregnant at the start of treatment.
• Contraception in women: highly effective contraception is required before starting, during treatment and for at least 7 months after the last dose. Because hormonal contraception is not recommended in patients with breast cancer, two complementary non-hormonal methods should be used.
• Contraception in men: male patients with female partners of reproductive potential or pregnant partners should use effective contraception (even after vasectomy) during treatment and for at least 4 months after the final dose.
• Pregnancy: there are no data from pregnant women; animal studies showed embryo-foetal toxicity. Talazoparib is not recommended during pregnancy or for women of childbearing potential not using contraception.
• Breastfeeding: contraindicated during treatment and for at least 1 month after the final dose.
• Fertility: there is no information on fertility in patients; the SmPC gives further detail.

Effect on Driving

Talzenna has a minor influence on the ability to drive and use machines; fatigue, asthenia or dizziness may occur. When it is given with enzalutamide, see also the enzalutamide product information.

Talzenna capsules do not require any special storage conditions. Keep out of the sight and reach of children.

4 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on restricted medical prescription: treatment is initiated and supervised by a physician experienced in the use of anticancer medicinal products. Talazoparib capsules are taken at home, so they are supplied to the patient or to the treating clinic on prescription.