4.1. Therapeutic indications

Breast cancer

Talzenna is indicated as monotherapy for the treatment of adult patients 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 patients were not suitable for these treatments (see section 5.1). 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

Talzenna is indicated in combination with enzalutamide for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated.

4.2. Posology and method of administration

Treatment with Talzenna should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Patient selection

Breast cancer

Patients should be selected for the treatment of breast cancer with Talzenna based on the presence of deleterious or suspected deleterious germline BRCA mutations determined by an experienced laboratory using a validated test method.

Genetic counselling for patients with BRCA mutations should be performed according to local regulations, as applicable.

Prostate cancer

There is no requirement for tumour mutation testing for selection of patients with mCRPC for treatment with Talzenna.

Posology

Talzenna monotherapy (breast cancer)

The recommended dose is 1 mg talazoparib once daily. Patients should be treated until disease progression or unacceptable toxicity occurs.

Talzenna in combination with enzalutamide (prostate cancer)

The recommended dose is 0.5 mg talazoparib in combination with 160 mg enzalutamide once daily. Patients should be treated until disease progression or unacceptable toxicity occurs.

Medical castration with luteinising hormone releasing hormone (LHRH) analogue should be continued during treatment in patients not surgically castrated.

Please refer to the full enzalutamide product information for the recommended posology.

Missing dose

If the patient vomits or misses a dose of Talzenna, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.

Dose adjustments

To manage adverse drug reactions, interruption of treatment or dose reduction based on severity and clinical presentation should be considered (see Table 1). Recommended dose reduction levels for talazoparib monotherapy (breast cancer) and for talazoparib when used in combination with enzalutamide (prostate cancer) are indicated in Table 2 and Table 3, respectively.

Complete blood count should be obtained prior to starting talazoparib therapy and monitored monthly and as clinically indicated (see Table 1 and section 4.4).

Table 1. Dose adjustments for adverse reactions

Withhold Talzenna until levels resolve to

Resume Talzenna

Haemoglobin < 8 g/dL

≥ 9 g/dL

Resume Talzenna at next lower dose

Platelet count < 50 000/μL

≥ 75 000/μL

Neutrophil count < 1 000/μL

≥ 1 500/µL

Non-haematologic adverse reaction Grade 3 or Grade 4

≤ Grade 1

Consider resuming Talzenna at next lower dose or discontinue

Table 2. Dose reduction levels for talazoparib monotherapy (breast cancer)

Talazoparib dose level (breast cancer)

Recommended starting dose

1 mg once daily

First dose reduction

0.75 mg once daily

Second dose reduction

0.5 mg once daily

Third dose reduction

0.25 mg once daily

Table 3. Dose reduction levels for talazoparib when used in combination with enzalutamide (prostate cancer)

Talazoparib dose level (prostate cancer)

Recommended starting dose

0.5 mg once daily

First dose reduction

0.35 mg once daily

Second dose reduction

0.25 mg once daily

Third dose reduction

0.1 mg once daily

Please refer to the full enzalutamide product information for dose adjustment for adverse reactions associated with enzalutamide.

The intended use of the 0.1 mg capsule is to support dose modifications and it is not interchangeable with other strengths.

Concomitant treatment with inhibitors of P-glycoprotein (P‑gp)

Talzenna 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 Talzenna dose should be reduced to the next lower dose. When the strong P-gp inhibitor is discontinued, the Talzenna 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 (see section 4.5).

Talzenna 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 (see section 4.5).

Special populations

Hepatic impairment

No dose adjustment is required for patients with mild hepatic impairment (total bilirubin ≤ 1 × upper limit of normal [ULN] and aspartate aminotransferase (AST) > ULN, or total bilirubin > 1.0 to 1.5 × ULN and any AST), moderate hepatic impairment (total bilirubin > 1.5 to 3.0 × ULN and any AST), or severe hepatic impairment (total bilirubin > 3.0 × ULN and any AST) (see section 5.2).

Talzenna 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 (see section 5.2).

Renal impairment

Breast cancer

No dose adjustment is required for patients with mild renal impairment (60 mL/min ≤ creatinine clearance [CrCL] < 90 mL/min). For patients with moderate renal impairment (30 mL/min ≤ CrCL < 60 mL/min), the recommended starting dose of Talzenna is 0.75 mg once daily. For patients with severe renal impairment (15 mL/min ≤ CrCL < 30 mL/min), the recommended starting dose of Talzenna is 0.5 mg once daily. Talzenna has not been studied in patients with CrCL < 15 mL/min or patients requiring haemodialysis (see section 5.2).

Prostate cancer

No dose adjustment is necessary for patients with mild renal impairment (60 mL/min ≤ creatinine clearance [CrCL] < 90 mL/min). For patients with moderate renal impairment (30 mL/min ≤ CrCL < 60 mL/min), the recommended dose of Talzenna 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 Talzenna is 0.25 mg once daily in combination with enzalutamide once daily. Talzenna has not been studied in patients with CrCL < 15 mL/min or patients requiring haemodialysis (see section 5.2).

Elderly

No dose adjustment is necessary in elderly (≥ 65 years of age) patients (see section 5.2).

Paediatric population

The safety and efficacy of Talzenna in children and adolescents < 18 years of age have not been established. No data are available.

Method of administration

Talzenna is for oral use. To avoid contact with the capsule content, the capsules should be swallowed whole, and must not be opened or dissolved. They can be taken with or without food (see section 5.2).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast-feeding (see section 4.6).

4.4. Special warnings and precautions for use

Myelosuppression

Myelosuppression consisting of anaemia, leukopenia/neutropenia, and/or thrombocytopenia, have been reported in patients treated with talazoparib (see section 4.8). Talazoparib should not be started until patients have recovered from haematological toxicity caused by previous therapy (≤ Grade 1).

Precautions should be taken to routinely monitor haematology parameters and signs and symptoms associated with anaemia, leukopenia/neutropenia, and/or thrombocytopenia in patients receiving talazoparib. If such events occur, dose modifications (reduction or interruption) are recommended (see section 4.2). Supportive care with or without blood and/or platelet transfusions and/or administration of colony stimulating factors may be used as appropriate.

Myelodysplastic syndrome/Acute myeloid leukaemia

Myelodysplastic syndrome/Acute Myeloid Leukaemia (MDS/AML) have been reported in patients who received poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, including talazoparib. Overall, MDS/AML has been reported in < 1% of solid tumour patients treated with talazoparib in clinical studies (see section 4.8). Potential contributing factors for the development of MDS/AML include previous platinum-containing chemotherapy, other DNA damaging agents or radiotherapy. Complete blood counts should be obtained at baseline and monitored monthly for signs of haematologic toxicity during treatment. If MDS/AML is confirmed, talazoparib should be discontinued.

Venous thromboembolic events

In patients with mCRPC a higher incidence of venous thromboembolic events was observed with Talzenna in combination with enzalutamide compared with enzalutamide alone. Patients should be monitored for clinical signs and symptoms of deep venous thrombosis and pulmonary embolism and treated as medically appropriate (see section 4.8).

Contraception in women of childbearing potential

Talazoparib was clastogenic in an in vitro chromosomal aberration assay in human peripheral blood lymphocytes and in an in vivo bone marrow micronucleus assay in rats but not mutagenic in Ames assay (see section 5.3), and may cause foetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the foetus (see section 4.6). Women of childbearing potential should not become pregnant while receiving Talzenna 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.

A highly effective method of contraception is required for female patients during treatment with Talzenna, and for at least 7 months after completing therapy. Since the use of hormonal contraception is not recommended in patients with breast cancer, two non-hormonal and complementary contraception methods should be used (see section 4.6).

Male patients with female partners of reproductive potential or pregnant partners should be advised to use effective contraception (even after vasectomy), during treatment with Talzenna and for at least 4 months after the final dose.

4.5. Interaction with other medicinal products and other forms of interaction

Talazoparib is a substrate for drug transporters P-gp and breast cancer resistance protein (BCRP) and it is mainly eliminated by renal clearance as unchanged compound.

Agents that may affect talazoparib plasma concentrations

P-gp inhibitors

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 (Ctrough) concentration reported for talazoparib 1 mg daily (see section 5.2). When Talzenna is co-administered with enzalutamide, the Talzenna starting dose is 0.5 mg (see section 4.2). 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 Talzenna 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 (AUCinf) and peak concentration (Cmax) 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 Talzenna dose should be reduced (see section 4.2).

P-gp inducers

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 Cmax by approximately 37% whereas AUCinf 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.

BCRP inhibitors

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.

Effect of acid-reducing agents

Population PK analysis indicates that co-administration of acid-reducing agents including proton pump inhibitors and histamine receptor 2 antagonists (H2RA), or other acid‑reducing agents had no significant impact on the absorption of talazoparib.

Systemic hormonal contraception

Drug-drug interaction studies between talazoparib and oral contraceptives have not been conducted.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should not become pregnant while receiving Talzenna 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 (see section 4.4).

Women of childbearing potential must use highly effective forms of contraception (see section 4.4) 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 Talzenna, and for at least 4 months after the final dose (see section 4.4).

Pregnancy

There are no data from the use of Talzenna in pregnant women. Studies in animals have shown embryo‑foetal toxicity (see section 5.3). Talzenna may cause foetal harm when administered to a pregnant woman. Talzenna is not recommended during pregnancy or for women of childbearing potential not using contraception (see section 4.4).

Breast-feeding

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 (see section 4.3) during treatment with Talzenna and for at least 1 month 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), Talzenna may impair fertility in males of reproductive potential (see section 5.3).

4.7. Effects on ability to drive and use machines

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

When Talzenna 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.

4.8. Undesirable effects

Summary of the safety profile

The overall safety profile of Talzenna 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 Talzenna 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 Talzenna; 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 Talzenna due to adverse reactions occurred in 62.1% of patients with mCRPC receiving Talzenna in combination with enzalutamide; the most common was anaemia (44%). Dose reductions of Talzenna due to adverse reactions occurred in 52.8% of patients; the most common was anaemia (43.2%). Permanent discontinuation of Talzenna 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 4 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 4. Adverse reactions based on pooled dataset from 8 studies (N=1 088)

System organ class

Frequency

Preferred term

All grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon

Myelodysplastic syndrome/Acute myeloid leukaemiaa

2 (0.2)

1 (< 0.1)

1 (< 0.1)

Blood and lymphatic system disorders

Very common

Thrombocytopeniab

Anaemiac

Neutropeniad

Leukopeniae

Very common

Lymphopeniaf

274 (25.2)

605 (55.6)

330 (30.3)

195 (17.9)

88 (8.1)

88 (8.1)

411 (37.8)

163 (15.0)

52 (4.8)

37 (3.4)

33 (3.0)

16 (1.5)

17 (1.6)

2 (0.2)

4 (0.4)

Metabolism and nutrition disorders

Very common

Decreased appetite

230 (21.1)

11 (1.0)

0 (0.0)

Nervous system disorders

Very common

Dizziness

Headache

Common

Dysgeusia

157 (14.4)

207 (19.0)

68 (6.3)

4 (0.4)

8 (0.7)

0 (0.0)

1 (< 0.1)

N/A

0 (0.0)

Vascular disorders

Common

Venous thromboembolism*g

36 (3.3%)

23 (2.1%)

2 (0.2%)

Gastrointestinal disorders

Very common

Vomiting

Diarrhoea

Nausea

Abdominal painh

Common

Stomatitis

Dyspepsia

167 (15.3)

205 (18.8)

389 (35.8)

162 (14.9)

54 (5.0)

69 (6.3)

9 (0.8)

4 (0.4)

10 (0.9)

12 (1.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

N/A

N/A

0 (0.0)

N/A

Skin and subcutaneous tissue disorders

Very common

Alopecia

189 (17.4)

N/A

N/A

General disorders and administration site conditions

Very common

Fatiguei

571 (52.5)

58 (5.3)

N/A

Abbreviations: n=number of patients; N/A=not applicable.

* Grade 5 adverse reactions were reported.

a. See also section 4.4.

b. Includes preferred terms of thrombocytopenia and platelet count decreased.

c. Includes preferred terms of anaemia, haematocrit decreased, haemoglobin decreased and red blood cell count decreased.

d. Includes preferred terms of neutropenia and neutrophil count decreased.

e. Includes preferred terms of leukopenia and white blood cell count decreased.

f. Includes preferred terms of lymphocyte count decreased and lymphopenia.

g. Includes preferred terms of pulmonary embolism, deep vein thrombosis, embolism venous and venous thrombosis. See also section 4.4.

h. Includes preferred terms of abdominal pain, abdominal pain upper, abdominal discomfort and abdominal pain lower.

i. 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is limited experience of overdose with talazoparib. No adverse reactions were reported in one patient who accidentally self-administered thirty 1 mg capsules of talazoparib on Day 1 and was immediately treated with gastric decontamination. Symptoms of overdose are not established. In the event of overdose, treatment with talazoparib should be stopped, and physicians should consider gastric decontamination, follow general supportive measures and treat symptomatically.