Talazoparib

The effect of BCRP inhibitors on PK of talazoparib has not been studied in vivo. Co-administration of talazoparib with BCRP inhibitors may increase talazoparib exposure. Concomitant use of strong BCRP inhibitors (including but not limited to curcumin and cyclosporine) should be avoided. If co-administration of strong BCRP inhibitors cannot be avoided, patient should be monitored for potential increased adverse reactions.

Data from a drug-drug interaction study in patients with advanced solid tumours indicated that co-administration of single 1 mg talazoparib dose with multiple daily doses of a P-gp inducer, rifampin 600 mg, with rifampin co-administered 30 minutes before talazoparib on the day of talazoparib dosing, increased talazoparib C_max by approximately 37% whereas AUC_inf was not affected relative to a single 1 mg talazoparib dose administered alone. This is probably the net effect of both P-gp induction and inhibition by rifampin under the tested conditions in the drug-drug interaction study. No talazoparib dose adjustments are required when co-administered with rifampin. However, the effect of other P-gp inducers on talazoparib exposure has not been studied. Other P-gp inducers (including but not limited to carbamazepine, phenytoin, and St. John’s wort) may decrease talazoparib exposure.

Talazoparib monotherapy (breast cancer)

Strong inhibitors of P-gp may lead to increased talazoparib exposure. Concomitant use of strong P-gp inhibitors during treatment with talazoparib should be avoided. Co-administration should only be considered after careful evaluation of the potential benefits and risks. If co-administration with a strong P-gp inhibitor is unavoidable, the talazoparib dose should be reduced to the next lower dose. When the strong P-gp inhibitor is discontinued, the talazoparib dose should be increased (after 3-5 half-lives of the P-gp inhibitor) to the dose used prior to the initiation of the strong P-gp inhibitor.

Talazoparib when used in combination with enzalutamide (prostate cancer)

The effect of co-administration of P-gp inhibitors on talazoparib exposure when talazoparib is given in combination with enzalutamide has not been studied. Therefore, concomitant use of P-gp inhibitors during treatment with talazoparib should be avoided.

Effect of enzalutamide

Co-administration with 160 mg enzalutamide increases talazoparib exposure approximately 2-fold. Administration of talazoparib 0.5 mg daily in combination with enzalutamide achieves approximately the same steady-state trough (C_trough) concentration reported for talazoparib 1 mg daily. When talazoparib is co-administered with enzalutamide, the talazoparib starting dose is 0.5 mg. The interaction effect of doses other than 160 mg enzalutamide on talazoparib has not been quantified. The effect of co-administration of other P-gp inhibitors on talazoparib exposure when talazoparib is given in combination with enzalutamide has not been studied. If co-administration of P-gp inhibitors cannot be avoided, when talazoparib is given with enzalutamide, the patient should be monitored for potential increased adverse reactions.

Effect of other P-gp inhibitors

Data from a drug-drug interaction study in patients with advanced solid tumours indicated that co-administration of multiple daily doses of a P-gp inhibitor, itraconazole 100 mg twice daily with a single 0.5 mg talazoparib dose increased talazoparib total exposure (AUC_inf) and peak concentration (C_max) by approximately 56% and 40%, respectively, relative to a single 0.5 mg talazoparib dose administered alone. Population pharmacokinetic (PK) analysis has also shown that concomitant use of strong P-gp inhibitors increased talazoparib exposure by 45%, relative to talazoparib given alone.

Concomitant use of strong P-gp inhibitors (including but not limited to amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, and verapamil) should be avoided. If co-administration with a strong P-gp inhibitor is unavoidable, the talazoparib dose should be reduced.

Breast cancer

For patients with moderate renal impairment (30 mL/min ≤ CrCL < 60 mL/min), the recommended starting dose of talazoparib is 0.75 mg once daily. For patients with severe renal impairment (15 mL/min ≤ CrCL < 30 mL/min), the recommended starting dose of talazoparib is 0.5 mg once daily. Talazoparib has not been studied in patients with CrCL < 15 mL/min or patients requiring haemodialysis.

Prostate cancer

For patients with moderate renal impairment (30 mL/min ≤ CrCL < 60 mL/min), the recommended dose of talazoparib is 0.35 mg once daily in combination with enzalutamide orally once daily. For patients with severe renal impairment (15 mL/min ≤ CrCL < 30 mL/min), the recommended dose of talazoparib is 0.25 mg once daily in combination with enzalutamide once daily. Talazoparib has not been studied in patients with CrCL < 15 mL/min or patients requiring haemodialysis.

Talazoparib in combination with enzalutamide is not recommended for use in patients with severe hepatic impairment (Child-Pugh classification C), as pharmacokinetics and safety have not been established in these patients.

There is no information on fertility in patients. Based on non-clinical findings in testes (partially reversible) and ovary (reversible), talazoparib may impair fertility in males of reproductive potential.

There are no data from the use of talazoparib in pregnant women. Studies in animals have shown embryo-foetal toxicity. Talazoparib may cause foetal harm when administered to a pregnant woman. Talazoparib is not recommended during pregnancy or for women of childbearing potential not using contraception.

It is unknown whether talazoparib is excreted in human breast milk. A risk to breast-fed children cannot be excluded and therefore breast-feeding is contraindicated during treatment with talazoparib and for at least 1 month after the final dose.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should not become pregnant while receiving talazoparib and should not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment.

Women of childbearing potential must use highly effective forms of contraception prior to starting treatment with talazoparib, during treatment, and for 7 months after stopping treatment with talazoparib. Since the use of hormonal contraception is not recommended in patients with breast cancer, two non-hormonal and complementary contraception methods should be used. Male patients with female partners of reproductive potential or pregnant partners should be advised to use effective contraception (even after vasectomy) during treatment with talazoparib, and for at least 4 months after the final dose.

Fertility

There is no information on fertility in patients. Based on non-clinical findings in testes (partially reversible) and ovary (reversible), talazoparib may impair fertility in males of reproductive potential.

Talazoparib has a minor influence on the ability to drive and use machines. Fatigue/asthenia or dizziness may occur following administration of talazoparib.

When talazoparib is given in combination with enzalutamide, please also refer to the full enzalutamide product information for the effects of enzalutamide on ability to drive and use machines.

Summary of the safety profile

The overall safety profile of talazoparib is based on pooled data from 1 088 patients, including 690 patients who received talazoparib monotherapy at 1 mg daily in clinical studies for solid tumours and 398 patients with mCRPC who received talazoparib 0.5 mg in combination with enzalutamide 160 mg in the TALAPRO-2 study.

The most common (≥20%) adverse reactions in patients receiving talazoparib in these clinical studies were anaemia (55.6%), fatigue (52.5%), nausea (35.8%), neutropenia (30.3%), thrombocytopenia (25.2%) and decreased appetite (21.1%). The most common (≥10%) Grade ≥3 adverse reactions of talazoparib were anaemia (39.2%), neutropenia (16.5%) and thrombocytopenia (11.1%).

Dose modifications (dose reductions or dose interruptions) due to any adverse reaction occurred in 58.7% of patients receiving talazoparib 1 mg monotherapy. The most common adverse reactions leading to dose modifications were anaemia (33.5%), neutropenia (11.7%) and thrombocytopenia (9.9%). Permanent discontinuation due to an adverse reaction occurred in 2.9% of patients receiving talazoparib; the most common was anaemia (0.6%). The median duration of exposure was 5.6 months (range 0.0 to 70.2).

Dose interruptions of talazoparib due to adverse reactions occurred in 62.1% of patients with mCRPC receiving talazoparib in combination with enzalutamide; the most common was anaemia (44%). Dose reductions of talazoparib due to adverse reactions occurred in 52.8% of patients; the most common was anaemia (43.2%). Permanent discontinuation of talazoparib due to adverse reactions occurred in 18.8% of patients; the most common was anaemia (8.3%). The median duration of talazoparib exposure was 86 weeks (range 0.29 to 186.14).

Tabulated list of adverse reactions

Table 3 summarises adverse reactions based on pooled dataset listed by system organ class, and frequency category. Frequency categories are defined as: very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1 000 to <1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3. Adverse reactions based on pooled dataset from 8 studies (N=1 088):

Abbreviations: n=number of patients; N/A=not applicable.
^* Grade 5 adverse reactions were reported.

^a Includes preferred terms of thrombocytopenia and platelet count decreased.
^b Includes preferred terms of anaemia, haematocrit decreased, haemoglobin decreased and red blood cell count decreased.
^c Includes preferred terms of neutropenia and neutrophil count decreased.
^d Includes preferred terms of leukopenia and white blood cell count decreased.
^e Includes preferred terms of lymphocyte count decreased and lymphopenia.
^f Includes preferred terms of pulmonary embolism, deep vein thrombosis, embolism venous and venous thrombosis.
^g Includes preferred terms of abdominal pain, abdominal pain upper, abdominal discomfort and abdominal pain lower.
^h Includes preferred terms of fatigue and asthenia.

Description of selected adverse reactions

Myelosuppression

Myelosuppression-related adverse reactions of anaemia, neutropenia and thrombocytopenia were very commonly reported in patients treated with talazoparib. Grade 3 and Grade 4 myelosuppression-related events were reported for anaemia in 37.8% and 1.5% of patients, neutropenia in 15.0% and 1.6%, and thrombocytopenia in 8.1% and 3.0%. No deaths were reported due to myelosuppression-related adverse reactions.

In monotherapy studies (1 mg/day population), the most frequent myelosuppression-related adverse events associated with dose modifications were anaemia (33.5%), neutropenia (11.7%) and thrombocytopenia (9.9%) reported for up to approximately 30% of patients in the talazoparib 1 mg/day population and the one associated with permanent study drug discontinuation was anaemia reported in 0.6% of patients.

In patients with mCRPC treated with talazoparib in combination with enzalutamide, anaemia led to talazoparib dose interruption in 44.0% of patients, decreased neutrophil count in 13.6%, and decreased platelet count in 7.8%. Overall, 42.5% of patients required blood transfusions. The most common blood transfusion was of packed red blood cells 39.2%. Discontinuation due to anaemia, neutropenia and thrombocytopenia occurred, respectively, in 8.3%, 3.3% and 0.5% of patients.