TALZENNA 1mg capsules medication leaflet

Talzenna 0.1 mg hard capsules

Talzenna 0.25 mg hard capsules

Talzenna 1 mg hard capsules

Talzenna 0.1 mg hard capsules

Each hard capsule contains talazoparib tosylate equivalent to 0.1 mg talazoparib.

Talzenna 0.25 mg hard capsules

Each hard capsule contains talazoparib tosylate equivalent to 0.25 mg talazoparib.

Talzenna 1 mg hard capsules

Each hard capsule contains talazoparib tosylate equivalent to 1 mg talazoparib.

For the full list of excipients, see section 6.1.

Hard capsule (capsule).

Talzenna 0.1 mg hard capsules

Opaque, approximately 14 mm × 5 mm hard capsule with a white cap (printed with “Pfizer” in black)and a white body (printed with “TLZ 0.1” in black).

Talzenna 0.25 mg hard capsules

Opaque, approximately 14 mm × 5 mm hard capsule with an ivory cap (printed with “Pfizer” in black)and a white body (printed with “TLZ 0.25” in black).

Talzenna 1 mg hard capsules

Opaque, approximately 14 mm × 5 mm hard capsule with a light red cap (printed with “Pfizer” inblack) and a white body (printed with “TLZ 1” in black).

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. Patientsshould have been previously treated with an anthracycline and/or a taxane in the (neo)adjuvant, locallyadvanced 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 priorendocrine-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 withmetastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinicallyindicated.

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

Patient selection

Breast cancer

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

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

Prostate cancer

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

Talzenna monotherapy (breast cancer)

The recommended dose is 1 mg talazoparib once daily. Patients should be treated until diseaseprogression 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 becontinued 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 nextprescribed dose should be taken at the usual time.

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

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

Table 1. Dose adjustments for adverse reactions

Withhold Talzenna until Resume Talzennalevels resolve to

Haemoglobin < 8 g/dL ≥ 9 g/dL

Resume Talzenna at next lower

Platelet count < 50 000/μL ≥ 75 000/μLdose

Neutrophil count < 1 000/μL ≥ 1 500/µL

Non-haematologic adverse Consider resuming Talzenna at≤ Grade 1reaction Grade 3 or Grade 4 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 reactionsassociated with enzalutamide.

The intended use of the 0.1 mg capsule is to support dose modifications and it is not interchangeablewith 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-gpinhibitors during treatment with talazoparib should be avoided. Co-administration should only beconsidered after careful evaluation of the potential benefits and risks. If co-administration with astrong 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 (after3-5 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 incombination with enzalutamide has not been studied. Therefore, concomitant use of P-gp inhibitorsduring treatment with talazoparib should be avoided (see section 4.5).

No dose adjustment is required for patients with mild hepatic impairment (total bilirubin ≤ 1 × upperlimit of normal [ULN] and aspartate aminotransferase (AST) > ULN, or total bilirubin > 1.0 to1.5 × 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 hepaticimpairment (Child-Pugh classification C), as pharmacokinetics and safety have not been established inthese patients (see section 5.2).

Breast cancer

No dose adjustment is required for patients with mild renal impairment (60 mL/min ≤ creatinineclearance [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 recommendedstarting 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 ≤ creatinineclearance [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 incombination 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 incombination with enzalutamide once daily. Talzenna has not been studied in patients with

CrCL < 15 mL/min or patients requiring haemodialysis (see section 5.2).

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

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

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

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

Breast-feeding (see section 4.6).

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

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

Myelodysplastic syndrome/Acute myeloid leukaemia

Myelodysplastic syndrome/Acute Myeloid Leukaemia (MDS/AML) have been reported in patientswho received poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, includingtalazoparib. Overall, MDS/AML has been reported in < 1% of solid tumour patients treated withtalazoparib 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 orradiotherapy. Complete blood counts should be obtained at baseline and monitored monthly for signsof haematologic toxicity during treatment. If MDS/AML is confirmed, talazoparib should bediscontinued.

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 bemonitored for clinical signs and symptoms of deep venous thrombosis and pulmonary embolism andtreated 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 bloodlymphocytes and in an in vivo bone marrow micronucleus assay in rats but not mutagenic in Amesassay (see section 5.3), and may cause foetal harm when administered to a pregnant woman. Pregnantwomen should be advised of the potential risk to the foetus (see section 4.6). Women of childbearingpotential should not become pregnant while receiving Talzenna and should not be pregnant at thebeginning of treatment. A pregnancy test should be performed on all women of childbearing potentialprior 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 contraceptionis not recommended in patients with breast cancer, two non-hormonal and complementarycontraception methods should be used (see section 4.6).

Male patients with female partners of reproductive potential or pregnant partners should be advised touse effective contraception (even after vasectomy), during treatment with Talzenna and for at least4 months after the final dose.

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

Agents that may affect talazoparib plasma concentrations

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 approximatelythe same steady-state trough (Ctrough) concentration reported for talazoparib 1 mg daily (seesection 5.2). When Talzenna is co-administered with enzalutamide, the Talzenna starting dose is0.5 mg (see section 4.2). The interaction effect of doses other than 160 mg enzalutamide ontalazoparib has not been quantified.

The effect of co-administration of other P-gp inhibitors on talazoparib exposure when talazoparib isgiven in combination with enzalutamide has not been studied. If co-administration of P-gp inhibitorscannot be avoided, when Talzenna is given with enzalutamide, the patient should be monitored forpotential increased adverse reactions.

Effect of other P-gp inhibitors

Data from a drug-drug interaction study in patients with advanced solid tumours indicated thatco-administration of multiple daily doses of a P-gp inhibitor, itraconazole 100 mg twice daily with asingle 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 doseadministered alone. Population pharmacokinetic (PK) analysis has also shown that concomitant use ofstrong 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 isunavoidable, 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 thatco-administration of single 1 mg talazoparib dose with multiple daily doses of a P-gp inducer, rifampin600 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 single1 mg talazoparib dose administered alone. This is probably the net effect of both P-gp induction andinhibition by rifampin under the tested conditions in the drug-drug interaction study. No talazoparibdose adjustments are required when co-administered with rifampin. However, the effect of other P-gpinducers on talazoparib exposure has not been studied. Other P-gp inducers (including but not limited tocarbamazepine, 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 oftalazoparib with BCRP inhibitors may increase talazoparib exposure. Concomitant use of strong

BCRP inhibitors (including but not limited to curcumin and cyclosporine) should be avoided. Ifco-administration of strong BCRP inhibitors cannot be avoided, patient should be monitored forpotential increased adverse reactions.

Effect of acid-reducing agents

Population PK analysis indicates that co-administration of acid-reducing agents including protonpump inhibitors and histamine receptor 2 antagonists (H2RA), or other acid-reducing agents had nosignificant impact on the absorption of talazoparib.

Systemic hormonal contraception

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

Women of childbearing potential should not become pregnant while receiving Talzenna and shouldnot be pregnant at the beginning of treatment. A pregnancy test should be performed on all women ofchildbearing 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 stoppingtreatment with talazoparib. Since the use of hormonal contraception is not recommended in patientswith 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 touse effective contraception (even after vasectomy) during treatment with Talzenna, and for at least4 months after the final dose (see section 4.4).

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

It is unknown whether talazoparib is excreted in human breast milk. A risk to breast-fed childrencannot be excluded and therefore breast-feeding is contraindicated (see section 4.3) during treatmentwith Talzenna and for at least 1 month after the final dose.

There is no information on fertility in patients. Based on non-clinical findings in testes (partiallyreversible) and ovary (reversible), Talzenna may impair fertility in males of reproductive potential (seesection 5.3).

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

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

The overall safety profile of Talzenna is based on pooled data from 1 088 patients, including690 patients who received talazoparib monotherapy at 1 mg daily in clinical studies for solid tumoursand 398 patients with mCRPC who received talazoparib 0.5 mg in combination with enzalutamide160 mg in the TALAPRO-2 study.

The most common (≥ 20%) adverse reactions in patients receiving talazoparib in these clinical studieswere 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 oftalazoparib were anaemia (39.2%), neutropenia (16.5%) and thrombocytopenia (11.1%).

Dose modifications (dose reductions or dose interruptions) due to any adverse reaction occurred in58.7% of patients receiving Talzenna 1 mg monotherapy. The most common adverse reactions leadingto 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 to70.2).

Dose interruptions of Talzenna due to adverse reactions occurred in 62.1% of patients with mCRPCreceiving Talzenna in combination with enzalutamide; the most common was anaemia (44%). Dosereductions of Talzenna due to adverse reactions occurred in 52.8% of patients; the most common wasanaemia (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 was86 weeks (range 0.29 to 186.14).

Table 4 summarises adverse reactions based on pooled dataset listed by system organ class, andfrequency 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 arepresented in order of decreasing seriousness.

Table 4. Adverse reactions based on pooled dataset from 8 studies (N=1 088)

System organ class

All grades Grade 3 Grade 4

Frequencyn (%) n (%) n (%)

Preferred term

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

Uncommon

Myelodysplastic syndrome/Acute myeloid 2 (0.2) 1 (< 0.1) 1 (< 0.1)leukaemiaa

Very common

Thrombocytopeniab 274 (25.2) 88 (8.1) 33 (3.0)

Anaemiac 605 (55.6) 411 (37.8) 16 (1.5)

Neutropeniad 330 (30.3) 163 (15.0) 17 (1.6)

Leukopeniae 195 (17.9) 52 (4.8) 2 (0.2)

Common

Lymphopeniaf 88 (8.1) 37 (3.4) 4 (0.4)

Very common

Decreased appetite 230 (21.1) 11 (1.0) 0 (0.0)

Very common

Dizziness 157 (14.4) 4 (0.4) 1 (< 0.1)

Headache 207 (19.0) 8 (0.7) N/A

Common

Dysgeusia 68 (6.3) 0 (0.0) 0 (0.0)

Common

Venous thromboembolism*g 36 (3.3%) 23 (2.1%) 2 (0.2%)

Very common

Vomiting 167 (15.3) 9 (0.8) 0 (0.0)

Diarrhoea 205 (18.8) 4 (0.4) 0 (0.0)

Nausea 389 (35.8) 10 (0.9) N/A

Abdominal painh 162 (14.9) 12 (1.1) N/A

Common

Stomatitis 54 (5.0) 0 (0.0) 0 (0.0)

Dyspepsia 69 (6.3) 0 (0.0) N/A

Very common

Alopecia 189 (17.4) N/A N/A

General disorders and administration siteconditions

Very common

Fatiguei 571 (52.5) 58 (5.3) N/A

Table 4. Adverse reactions based on pooled dataset from 8 studies (N=1 088)

System organ class

All grades Grade 3 Grade 4

Frequencyn (%) n (%) n (%)

Preferred term

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 countdecreased.

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 venousthrombosis. See also section 4.4.h. Includes preferred terms of abdominal pain, abdominal pain upper, abdominal discomfort and abdominal painlower.i. Includes preferred terms of fatigue and asthenia.

Myelosuppression-related adverse reactions of anaemia, neutropenia and thrombocytopenia were verycommonly reported in patients treated with talazoparib. Grade 3 and Grade 4myelosuppression-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 reporteddue to myelosuppression-related adverse reactions.

In monotherapy studies (1 mg/day population), the most frequent myelosuppression-related adverseevents associated with dose modifications were anaemia (33.5%), neutropenia (11.7%) andthrombocytopenia (9.9%) reported for up to approximately 30% of patients in the talazoparib1 mg/day population and the one associated with permanent study drug discontinuation was anaemiareported in 0.6% of patients.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, ATC code: L01XK04

Talazoparib is an inhibitor of PARP enzymes, PARP1 (IC50=0.7 nM), and PARP2 (IC50=0.3 nM).

PARP enzymes are involved in cellular DNA damage response signalling pathways such as DNArepair, gene transcription, and cell death. PARP inhibitors (PARPi) exert cytotoxic effects on cancercells by 2 mechanisms, inhibition of PARP catalytic activity and by PARP trapping, whereby PARPprotein bound to a PARPi does not readily dissociate from a DNA lesion, thus preventing DNA repair,replication, and transcription, thereby resulting in apoptosis and/or cell death. Treatment of cancer celllines that are harbouring defects in DNA repair genes with talazoparib single agent leads to increasedlevels of γH2AX, a marker of double stranded DNA breaks, and results in decreased cell proliferationand increased apoptosis. Talazoparib anti-tumour activity was also observed in a patient-derivedxenograft (PDX) BRCA mutant breast cancer model where the patient was previously treated with aplatinum-based regimen, as well as in an androgen receptor (AR)-positive prostate cancer xenograftmodel. In these PDX models talazoparib decreased tumour growth and increased γH2AX level andapoptosis in the tumours.

The anti-tumour effects of combined inhibition of PARP and AR activity is based on the followingmechanisms: AR signalling inhibition suppresses the expression of homologous recombination repair(HRR) genes including BRCA1, resulting in sensitivity to PARP inhibition. PARP1 activity has beenshown to be required for maximal AR function and thus inhibiting PARP may reduce AR signallingand increase sensitivity to AR signalling inhibitors. Clinical resistance to AR blockade is sometimesassociated with co-deletion of RB1 and BRCA2, which is in turn associated with sensitivity to PARPinhibition.

The effect of talazoparib on cardiac repolarisation was evaluated using time-matchedelectrocardiograms (ECGs) in assessing the relationship between the change of the QT intervalcorrected for heart rate (QTc) from baseline and the corresponding plasma talazoparib concentrationsin 37 patients with advanced solid tumours. Talazoparib did not have a clinically relevant effect on

QTc prolongation at the maximum clinically recommended monotherapy dose of 1 mg once daily.

Germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer

EMBRACA study

EMBRACA was an open-label, randomised, parallel, 2-arm multicentre study of Talzenna versuschemotherapy (capecitabine, eribulin, gemcitabine, vinorelbine) in patients with germline

BRCA-mutated HER2-negative locally advanced or metastatic breast cancer who received no morethan 3 prior cytotoxic chemotherapy regimens for their metastatic or locally advanced disease. Patientswere required to have received treatment with an anthracycline and/or a taxane (unlesscontraindicated) in the neoadjuvant, adjuvant and/or metastatic setting. Patients with prior platinumtherapy for advanced disease were required to have no evidence of disease progression duringplatinum therapy. No prior treatment with a PARPi was permitted.

Of the 431 patients randomised in the EMBRACA study, 408 (95%) were centrally confirmed to havea deleterious or suspected deleterious gBRCAm using a clinical study assay; out of which 354 (82%)were confirmed using the BRACAnalysis CDx. BRCA mutation status (breast cancer susceptibilitygene 1 [BRCA1] positive or breast cancer susceptibility gene 2 [BRCA2] positive) was similar acrossboth treatment arms.

A total of 431 patients were randomised 2:1 to receive Talzenna 1 mg capsules once daily orchemotherapy at standard doses until progression or unacceptable toxicity. Of the 431 patientsrandomised onto EMBRACA, 287 were randomised to the Talzenna arm and 144 to the chemotherapyarm. Randomisation was stratified by prior use of chemotherapy for metastatic disease (0 versus 1, 2,or 3), by triple-negative disease status (triple-negative breast cancer [TNBC] versus non-TNBC), andhistory of central nervous system metastasis (yes versus no).

Patient demographic, baseline, and disease characteristics were generally similar between the studytreatment arms (see Table 5).

Table 5. Demographic, baseline, and disease characteristics—EMBRACA study

Talazoparib Chemotherapy(N=287) (N=144)

Median age (y [range]) 45.0 (27.0, 84.0) 50.0 (24.0, 88.0)

Age category (y), n (%)< 50 182 (63.4%) 67 (46.5%)50 to < 65 78 (27.2%) 67 (46.5%)≥ 65 27 (9.4%) 10 (6.9%)

Gender, n (%)

Female 283 (98.6%) 141 (97.9%)

Male 4 (1.4%) 3 (2.1%)

Race, n (%)

Asian 31 (10.8%) 16 (11.1%)

Black or African American 12 (4.2%) 1 (0.7%)

White 192 (66.9%) 108 (75.0%)

Other 5 (1.7%) 1 (0.7%)

Not reported 47 (16.4%) 18 (12.5%)

ECOG performance status, n (%)0 153 (53.3%) 84 (58.3%)1 127 (44.3%) 57 (39.6%)2 6 (2.1%) 2 (1.4%)

Missing 1 (0.3%) 1 (0.7%)

Hormone receptor status, n (%)

HER2-positive 0 (0.0%) 0 (0.0%)

Triple-negative 130 (45.3%) 60 (41.7%)

Hormone receptor-positive (ER positive or 157 (54.7%) 84 (58.3%)

PgR positive)

BRCA status by central or local laboratory assessment, 287 (100.0%) 144 (100.0%)n (%)

BRCA1-mutation positive 133 (46.3%) 63 (43.8%)

BRCA2-mutation positive 154 (53.7%) 81 (56.3%)

Time from initial diagnosis of breast cancer to diagnosis of advanced breast cancer (years)n 286 144

Median 1.9 2.7

Minimum, maximum 0, 22 0, 24

Categories for time from initial diagnosis of breast cancer to diagnosis of advanced breast cancer< 12 months 108 (37.6%) 42 (29.2%)≥ 12 months 178 (62.0%) 102 (70.8%)

Number of prior cytotoxic regimens for locally advanced or metastatic disease

Mean (Std Dev) 0.9 (1.01) 0.9 (0.89)

Median 1 1

Minimum, maximum 0, 4 0, 3

Table 5. Demographic, baseline, and disease characteristics—EMBRACA study

Talazoparib Chemotherapy(N=287) (N=144)

Number of patients who received prior cytotoxic regimens for locally advanced or metastaticdisease, n (%)0 111 (38.7%) 54 (37.5%)1 107 (37.3%) 54 (37.5%)2 57 (19.9%) 28 (19.4%)3 11 (3.8%) 8 (5.6%)≥ 4 1 (0.3%) 0 (0.0%)

Number of patients who received following prior therapies, n (%)

Taxane 262 (91.3%) 130 (90.3%)

Anthracycline 243 (84.7%) 115 (79.9%)

Platinum 46 (16.0%) 30 (20.8%)

Abbreviations: BRCA=breast cancer susceptibility gene; ER=estrogen receptor; HER2=human epidermalgrowth factor receptor 2; N=number of patients; n=number of patients in category; PgR=progesterone receptor.

The primary efficacy endpoint was progression-free survival (PFS) evaluated according to Response

Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by blinded independent centralreview (BICR). The secondary objectives were objective response rate (ORR), overall survival (OS),safety, and PK.

The study demonstrated a statistically significant improvement in PFS, the primary efficacy outcome,for Talzenna compared with chemotherapy. There was no statistically significant effect on OS at thetime of final OS analysis. Efficacy data for EMBRACA are summarised in Table 6. The Kaplan-Meiercurves for PFS and OS are displayed in Figure 1 and Figure 3, respectively.

Table 6. Summary of efficacy results—EMBRACA study*

Talazoparib Chemotherapy

PFS by BICR N=287 N=144

Events, number (%) 186 (65%) 83 (58%)

Median (95% CI), months 8.6 (7.2, 9.3) 5.6 (4.2, 6.7)

Hazard ratioa (95% CI) 0.54 (0.41, 0.71)2-sided p-valueb p<0.0001

OS (final analysis)c N=287 N=144

Events, number (%) 216 (75.3%) 108 (75%)

Median (95% CI), months 19.3 (16.6, 22.5) 19.5 (17.4, 22.4)

Hazard ratioa (95% CI) 0.85 (0.67, 1.07)c2-sided p-valueb p=0.1693

Objective response by investigatord,e N=219 N=114

ORR, % (95% CI) 62.6 (55.8, 69.0) 27.2 (19.3, 36.3)

Odds ratio (95% CI) 4.99 (2.93, 8.83)2-sided p-valuef p<0.0001

Duration of response by investigatord N=137 N=31

Median (IQR), months 5.4 (2.8, 11.2) 3.1 (2.4, 6.7)

Table 6. Summary of efficacy results—EMBRACA study*

Talazoparib Chemotherapy

Abbreviations: BICR=blinded independent central review; CI=confidence interval;

CMH=Cochran-Mantel-Haenszel; CR=complete response; IQR=interquartile range; ITT=intent-to-treat;

N=number of patients; ORR=objective response rate; OS=overall survival; PARP=poly (adenosinediphosphate-ribose) polymerase; PFS=progression-free survival; PR=partial response;

RECIST 1.1=Response Evaluation Criteria in Solid Tumors version 1.1.

* PFS, ORR and Duration of response are based on the data cutoff date of 15 September 2017 and amedian follow-up for PFS of 13.0 months (95% CI: 11.1, 18.4) in the talazoparib arm and 7.2 months(95% CI: 4.6, 11.1) in the chemotherapy arm. OS is based on the data cutoff date 30 September 2019and a median follow-up of 44.9 months (95% CI: 37.9, 47.0) in the talazoparib arm and 36.8 months(95% CI: 34.3, 43.0) in the chemotherapy arm.

a. Hazard ratio was based on stratified Cox regression model with treatment as the only covariate(stratification factors: number of prior cytotoxic chemotherapy regimens, triple-negative status, historyof central nervous system metastasis) and was relative to overall chemotherapy with < 1 favouringtalazoparib.

b. Stratified log-rank test.

c. At the time of the final OS analysis, 46.3% versus 41.7% of patients randomised in the talazoparib andchemotherapy arms, respectively, received subsequently a platinum therapy, and 4.5% versus 32.6%received subsequently a PARP inhibitor treatment.

d. Conducted in ITT with measurable disease population who had an objective response. The completeresponse rate was 5.5% for talazoparib compared to 0% for the chemotherapy arm.

e. Per RECIST 1.1, confirmation of CR/PR was not required.

f. Stratified CMH test.

Figure 1. Kaplan-Meier curves of PFS—EMBRACA study100 Talazoparib

Median PFS=8.6 months90 95% CI (7.2, 9.3)

Chemotherapy

Median PFS=5.6 months95% CI (4.2, 6.7)

Hazard Ratio=0.5460 95% CI (0.41, 0.71)p<0.00010 3 6 9 12 15 18 21 24 27 30 33 36 39

Time (Month)

Number of patients at risk

Talazoparib 287 229 148 91 55 42 29 23 16 12 5 3 1

Chemotherapy 144 68 34 22 9 8 4 2 2 1

Abbreviations: CI=confidence interval; PFS=progression-free survival.

A series of prespecified subgroup PFS analyses was performed based on prognostic factors andbaseline characteristics to investigate the internal consistency of treatment effect. Consistent with theoverall results, a reduction in the risk of disease progression or death in favour of the talazoparib armwas observed in all individual patient subgroups (Figure 2).

Progression-Free Survival Probability (%)

Figure 2. Forest plot of PFS analyses for key subgroups—EMBRACA study

Abbreviations: aBC=advanced breast cancer; CI=confidence interval; CNS=central nervous system; HR+=hormonereceptor-positive; ITT=intent-to-treat; PCT=physician’s choice treatment (chemotherapy); PFS=progression-freesurvival; TNBC=triple-negative breast cancer.

Figure 3 Kaplan-Meier curves of overall survival—EMBRACA study

Abbreviations: CI=confidence interval; OS=overall survival.

Primary analysis’ p-value was based on a stratified log-rank test.

Metastatic castration-resistant prostate cancer (mCRPC)

TALAPRO-2 study

TALAPRO-2 was a randomised, double-blind, placebo-controlled study in which patients (N=805)with mCRPC were randomised 1:1 to receive Talzenna 0.5 mg once daily in combination withenzalutamide 160 mg once daily, versus a comparator arm of placebo in combination withenzalutamide 160 mg once daily. All patients received a gonadotropin-releasing hormone (GnRH)analog or had prior bilateral orchiectomy and needed to have progressed on prior androgen deprivationtherapy. Prior treatment with abiraterone or taxane-based chemotherapy for metastaticcastration-sensitive prostate cancer (mCSPC) was permitted.

Randomisation was stratified by (1) previous treatment with abiraterone or taxane-basedchemotherapy versus no such prior treatment; and by (2) HRR gene mutation status which wasprospectively tested by next generation sequencing of tumour tissue using FoundationOne CDx orcirculating tumour DNA (ctDNA) using FoundationOne Liquid CDx; patients with tumour HRR genemutations (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN,

PALB2, or RAD51C) versus patients without tumour HRR gene mutations or with unknown status.

The median age was 71 years (range 36 to 91) in both arms; 62% were White, 31% were Asian, and2% were Black. Most participants (66%) in both arms had an ECOG performance status of 0. Inpatients treated with Talzenna, the proportion of patients with RECIST 1.1 measurable disease atbaseline per BICR was 30%. Twenty-eight percent (28%) of patients had received prior abiraterone ortaxane-based chemotherapy. Twenty percent (20%) had tumours with HRR gene mutations and 80%had tumours that did not have HRR gene mutations or had an unknown status.

The primary efficacy outcome was radiographic progression-free survival (rPFS) evaluated accordingto RECIST version 1.1 and Prostate Cancer Clinical Trials Working Group Criteria 3 (PCWG3)(bone) criteria, as assessed by BICR. OS was an alpha-controlled secondary endpoint.

A statistically significant improvement in BICR-assessed rPFS was demonstrated for Talzenna incombination with enzalutamide compared to placebo in combination with enzalutamide. A sensitivityanalysis of investigator-assessed rPFS was consistent with the BICR-assessed rPFS results.

Efficacy results of TALAPRO-2 are provided in Table 7 and Figure 4.

Table 7. Summary of efficacy results—TALAPRO-2 (mCRPC)*

Talazoparib + Placebo + enzalutamideenzalutamiderPFS by BICR N=402 N=403

Events, number (%) 151 (37.6) 191 (47.4)

Median months (95% CI) NR (27.5, NR) 21.9 (16.6, 25.1)

Hazard ratio (95% CI)a 0.627 (0.506, 0.777)p-valueb p<0.0001

Second interim OS

Events, number (%) 156 (38.8) 174 (43.2)

Median months (95% CI) NR (37.3, NR) 38.2 (34.1, 43.1)

Hazard ratio (95% CI)a 0.837 (0.674, 1.040)

Abbreviations: BICR=blinded independent central review; CI=confidence interval; CSPC=castration-sensitiveprostate cancer; HRR=homologous recombination repair; mCRPC=metastatic castration-resistant prostatecancer; N=number of patients; NHT=novel hormone therapy; NR=not reached; OS-overall survival;rPFS=radiographic progression-free survival.

* rPFS is based on the data cutoff date of 16 August 2022 and a median follow-up for rPFS of 24.9 months(95% CI: 24.7, 25.3) in the talazoparib plus enzalutamide arm and 24.6 months (95% CI: 22.1, 24.9) in theplacebo plus enzalutamide arm. Second interim OS is based on the data cutoff date 28 March 2023 and amedian follow-up of 35.8 months (95% CI: 33.6, 35.9) in the talazoparib plus enzalutamide arm and 34.6months (95% CI: 32.7, 35.9) in the placebo plus enzalutamide arm.a Hazard ratio based on Cox proportional hazards model stratified by previous treatment with NHT(abiraterone) or taxane-based chemotherapy for CSPC (yes versus no) and by HRR mutational status(deficient versus non-deficient/unknown) with < 1 favouring talazoparib.

b. P-values (2-sided) from the log-rank test stratified by previous treatment with NHT (abiraterone) ortaxane-based chemotherapy for CSPC and by HRR mutational status.

Table 8. Summary of efficacy results for subgroup analysis - TALAPRO-2 (mCRPC)*

Talazoparib + Placebo +enzalutamide enzalutamide

HRRm Subgroup Analysesa

HRRm N=85 N=82rPFS by BICR

Events, number (%) 37 (43.5) 49 (59.7)

Median months (95% CI) 27.9 (16.8, NR) 13.8 (10.9, 19.5)

Hazard ratio (95% CI)b 0.424 (0.275, 0.653)

Second interim OS

Events, number (%) 30 (35.3) 41 (50.0)

Median months (95% CI) 41.9 (36.4, NR) 30.8 (25.6, 38.8)

Hazard ratio (95% CI)b 0.516 (0.320, 0.831)

Non-HRRm N=207 N=219rPFS by BICR

Events, number (%) 73 (35.3) 95 (43.4)

Median months (95% CI) NR (25.8, NR) 22.4 (16.6, NR)

Hazard ratio (95% CI)b 0.695 (0.511, 0.944)

Second interim OS

Events, number (%) 82 (39.6) 96 (43.8)

Median months (95% CI) NR (33, NR) 38 (33.9, NR)

Hazard ratio (95% CI)b 0.880 (0.654, 1.182)

BRCAm Subgroup Analysesa

BRCAm N=27 N=32rPFS by BICR

Events, number (%) 8 (29.6) 22 (68.7)

Median months (95% CI) NR (16.8, NR) 11 (7.4, 24.6)

Hazard ratio (95% CI)b 0.232 (0.101, 0.529)

Second interim OS

Events, number (%) 12 (44.4) 18 (56.3)

Median months (95% CI) 41.9 (24.9, NR) 26.1 (15.2, NR)

Hazard ratio (95% CI)b 0.558 (0.263, 1.187)

Abbreviations: BICR=blinded independent central review; BRCAm=breast cancer gene mutated;

CI=confidence interval; CSPS=castration-sensitive prostate cancer; ctDNA=circulating tumour DNA;

HRRm=homologous recombination repair gene mutated; mCRPC=metastatic castration-resistant prostatecancer; N=number of patients; NHT=novel hormone therapy; NR=not reached; OS=overall survival;rPFS=radiographic progression-free survival.

* Based on the data cutoff date of 16 August 2022 and a median follow-up for rPFS of 24.9 months (95%

CI: 24.7, 25.3) in the talazoparib plus enzalutamide arm, and 24.6 months (95% CI: 22.1, 24.9) in theplacebo plus enzalutamide arm. Second interim OS is based on the data cutoff date 28 March 2023 and amedian follow-up of 35.8 months (95% CI: 33.6, 35.9) in the talazoparib plus enzalutamide arm and34.6 months (95% CI: 32.7, 35.9) in the placebo plus enzalutamide arm.

a. Derived based on prospective tumour tissue-based results (results known prior to randomisation) andprospective blood-based ctDNA results (results known prior to randomisation).b Hazard ratio based on Cox proportional hazard model stratified by previous treatment with NHT(abiraterone) or taxane-based chemotherapy for CSPC (yes versus no) with < 1 favouring talazoparib.

Figure 4. Kaplan-Meier curves of rPFS by BICR—TALAPRO-2 (mCRPC)

Abbreviations: BICR=blinded independent central review; CI=confidence interval; mCRPC=metastaticcastration-resistant prostate cancer; PFS=progression-free survival; rPFS=radiographic progression-free survival.

Figure 5. Forest plot of rPFS analyses for key subgroups—TALAPRO-2 (mCRPC)

Abbreviations: CI=confidence interval; ctDNA=circulating tumour DNA; ENZA=enzalutamide;

HRR=homologous recombination repair; HRRm=homologous recombination repair gene mutated;

IWRS=Interactive Web Response System; mCRPC=metastatic castration-resistant prostate cancer; N=number ofparticipants; NE=not evaluable/not reached; NHT=novel hormone therapy; PBO=placebo;

PSA=prostate-specific antigen; rPFS=radiographic progression-free survival; SE=study entry;

TALA=talazoparib; w/o=without.

Hazard ratio for all patients was based on a Cox model stratified by the randomization stratification factors. Forall subgroups, hazard ratio was based on an unstratified Cox model with treatment as the only covariate. Ahazard ratio < 1 favours talazoparib.

HRR status is derived based on prospective tumour tissue-based results and prospective blood-based ctDNAresults.

The European Medicines Agency has waived the obligation to submit the results of studies withtalazoparib in all subsets of the paediatric population in breast cancer and prostate cancer (see section4.2 for information on paediatric use).

Talazoparib exposure generally increased proportionally with dose across the range of 0.025 mg to2 mg after daily administration of multiple doses. Following repeated daily dosing of 1 mg talazoparibmonotherapy to breast cancer patients, the geometric mean (% coefficient of variation [CV%]) areaunder the plasma concentration-time curve (AUC) and maximum observed plasma concentration(Cmax) of talazoparib at steady-state was in the range of 126 (107) ng*hr/mL to 208 (37) ng*hr/mL and11 (90) ng/mL to 19 (27) ng/mL, respectively. After oral administration of 0.5 mg talazoparib oncedaily in combination with enzalutamide in patients with mCRPC, the geometric mean (CV%)steady-state Ctrough across visits ranged from 3.29 to 3.68 ng/mL (45 to 48%), which is similar to theobserved values of 3.53 (61%) ng/mL when talazoparib monotherapy was administered at 1 mg oncedaily in breast cancer patients. Following repeated daily dosing, talazoparib plasma concentrationsreached steady-state within 2 to 3 weeks when administered alone, and approximately within 9 weekswhen co-administered with enzalutamide. The median accumulation ratio of talazoparib followingrepeated oral administration of 1 mg monotherapy once daily was in the range of 2.3 to 5.2.

Talazoparib is a substrate of P-gp and BCRP transporters.

Following oral administration of talazoparib, the median time to Cmax (Tmax) was generally between1 to 2 hours after dosing. The absolute bioavailability study has not been conducted in humans.

However, based on urinary excretion data the absolute bioavailability is at least 41% with fractionabsorbed of at least 69% (see Elimination). No significant effect of acid-reducing agents ontalazoparib exposure is expected, given sufficient solubility of talazoparib at all pHs between 1 and6.8. Twenty-eight percent (28%) of the patients in the pivotal study were taking acid-reducing agents,mainly proton pump inhibitors.

The effect of food

Food intake decreased the rate but not the extent of talazoparib absorption. Following a single oraldose of talazoparib with high-fat, high-calorie food (approximately 827 calories, 57% fat), the mean

Cmax of talazoparib was decreased by approximately 46%, the median Tmax was delayed from 1 to4 hours, while the AUCinf was not affected. Based on these results, Talzenna can be administered withor without food (see section 4.2).

The population mean apparent volume of distribution (Vss/F) of talazoparib was 420 L. In vitro,talazoparib is approximately 74% bound to plasma proteins with no concentration dependence overthe concentration range of 0.01 µM to 1 µM. Renal or hepatic impairment does not appear to impacttalazoparib protein binding as there was no obvious trend in the mean talazoparib fraction of unbounddrug (fu) in human plasma in vivo with worsening renal function or hepatic function.

Talazoparib undergoes minimal hepatic metabolism in humans. Following oral administration of asingle 1 mg dose of [14C]talazoparib to humans, no major circulating metabolites were identified inplasma, and talazoparib was the only circulating drug-derived entity identified. No metabolites thatindividually represented more than 10% of the administered dose were recovered in the urine or faeces.

In vitro, talazoparib was not an inhibitor of cytochrome (CYP)1A2, CYP2B6, CYP2C8, CYP2C9,

CYP2C19, CYP2D6, or CYP3A4/5 or inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevantconcentrations.

In vitro, talazoparib did not inhibit any of the major intestinal, hepatic or renal membrane transporters(P-gp, BCRP, organic anion transporting polypeptide [OATP]1B1, OATP1B3, organic cationictransporter [OCT]1, OCT2, organic anion transporter [OAT]1, OAT3, bile salt export pump [BSEP],multidrug and toxin extrusion [MATE]1 and MATE2-K) at clinically relevant concentrations.

In vitro, talazoparib did not inhibit any of the major uridine-diphosphate glucuronosyltransferase(UGT) isoforms (1A1, 1A4, 1A6, 1A9, 2B7, and 2B15) at clinically relevant concentrations.

Renal elimination of unchanged drug (passive filtration and active secretion) is the major route oftalazoparib elimination. P-gp is likely involved in talazoparib active renal secretion. The mean(±standard deviation) terminal plasma half-life of talazoparib was 90 (±58) hours and the populationmean (inter-subject variability) apparent oral clearance (CL/F) was 6.5 (31%) L/h in cancer patients.

In 6 female patients given a single oral dose of [14C]talazoparib, a mean of 69% (±8.6%) and 20%(±5.5%) of the total administered radioactive dose was recovered in urine and faeces, respectively.

Excretion of unchanged talazoparib in urine was the major route of elimination accounting for 55% ofthe administered dose, while unchanged talazoparib recovered in the faeces accounted for 14%.

Age, sex, and body weight

A population PK analysis was conducted using data from 490 patients with cancer who receivedtalazoparib 1 mg daily as monotherapy to evaluate the impact of age (ranging from 18 to 88 years),sex (53 males and 437 females), and body weight (ranging from 35.7 kg to 162 kg) on the PK oftalazoparib. The results have shown that age, sex, and body weight had no clinically relevant effect onthe PK of talazoparib.

Based on a population PK analysis that included 490 patients who received talazoparib 1 mg daily asmonotherapy, where 41 patients were Asian and 449 patients were Non-Asian (361 White, 16 Black,9 Others, and 63 Not reported), talazoparib CL/F was higher in Asian patients compared to Non-Asianpatients, leading to 19% lower exposure (AUC) in Asian patients.

Pharmacokinetics of talazoparib have not been evaluated in patients < 18 years of age.

Talazoparib monotherapy

Data from a PK study in advanced cancer patients with varying degrees of renal impairment indicatedthat talazoparib total exposure (AUC0-24) after multiple talazoparib once daily doses increased by 92%and 169% in patients with moderate (eGFR 30 - < 60 mL/min) and severe (eGFR < 30 mL/min) renalimpairment, respectively, relative to patients with normal renal function (eGFR ≥ 90 mL/min).

Talazoparib Cmax increased by 90% and 107% in patients with moderate and severe renal impairment,respectively, relative to patients with normal renal function. Talazoparib exposure was similar forpatients with mild renal impairment (eGFR 60 - < 90 mL/min) and those with normal renal function.

In addition, based on a population PK analysis that included 490 patients, where 132 patients had mildrenal impairment (60 mL/min ≤ CrCL < 90 mL/min), 33 patients had moderate renal impairment(30 mL/min ≤ CrCL < 60 mL/min), and 1 patient had severe renal impairment(CrCL < 30 mL/min),talazoparib CL/F was decreased by 14% and 37% in patients with mild andmoderate renal impairment, corresponding to 17% and 59% increase in AUC, respectively, whencompared to patients with normal renal function (CrCL ≥ 90 mL/min). The PK of talazoparib have notbeen studied in patients requiring haemodialysis (see section 4.2).

Talazoparib co-administered with enzalutamide

Based on a population PK analysis that included 412 mCRPC patients who received talazoparibco-administered with enzalutamide, where 152 patients had mild renal impairment (60 mL/min≤ CrCL < 90 mL/min), 72 patients had moderate renal impairment (30 mL/min ≤ CrCL < 60 mL/min),and 2 patients had severe renal impairment (CrCL < 30 mL/min), talazoparib CL/F was decreased by8% and 27%, corresponding to increases of 9% and 37% in AUC, in patients with mild and moderaterenal impairment respectively, compared to patients with normal renal function. The PK of talazoparibhas not been studied in patients requiring haemodialysis (see section 4.2).

Talazoparib monotherapy

Based on a population PK analysis that included 490 patients who received talazoparib 1 mg daily asmonotherapy, where 118 patients had mild hepatic impairment (total bilirubin ≤ 1.0 × ULN and AST> ULN, or total bilirubin > 1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect onthe PK of talazoparib. The PK of talazoparib in patients with normal hepatic function, mild hepaticimpairment, moderate hepatic impairment (total bilirubin > 1.5 to 3.0 × ULN and any AST) or severehepatic impairment (total bilirubin > 3.0 × ULN and any AST) was studied in a PK study. Population

PK analysis using data from this PK study indicated that mild, moderate or severe hepatic impairment hadno significant impact on the PK of talazoparib (see section 4.2).

Talazoparib co-administered with enzalutamide

The PK of talazoparib in combination with enzalutamide has not been studied in patients with hepaticimpairment (see section 4.2).

Carcinogenicity studies have not been conducted with talazoparib.

Talazoparib was not mutagenic in a bacterial reverse mutation (Ames) test. Talazoparib was clastogenicin an in vitro chromosomal aberration assay in human peripheral blood lymphocytes and in an in vivomicronucleus assay in rats at exposures similar to clinically relevant doses. This clastogenicity isconsistent with genomic instability resulting from the primary pharmacology of talazoparib, indicatingthe potential for genotoxicity in humans.

In repeat-dose toxicity studies in rats and in dogs, the main findings at subtherapeutic exposuresincluded bone marrow hypocellularity with dose-dependent decrease in haematopoietic cells, depletionof lymphoid tissue in multiple organs and atrophy and/or degenerative changes in testes, epididymisand seminiferous tubules. Additional findings at higher exposures included dose-dependent increase inapoptosis/necrosis in the gastrointestinal (GI) tract, liver and ovary. Most of the histopathologicfindings were generally reversible while the testes findings were partially reversible after 4 weeks ofdosing cessation. These toxicity findings are consistent with the pharmacology of talazoparib and itstissue distribution pattern.

Developmental toxicology

In an embryo-foetal development study in rats, talazoparib resulted in embryo-foetal death, foetalmalformation (depressed eye bulge, small eye, split sternebrae, fused cervical vertebral arch) andstructural variations in bones at a maternal systemic AUC24 exposure approximately 0.09-fold therelevant human exposure at the recommended dose.

Silicified microcrystalline cellulose (microcrystalline cellulose and silicone dioxide)0.1 mg capsule shell

Hypromellose

Titanium dioxide (E171)0.25 mg capsule shell

Hypromellose

Yellow iron oxide (E172)

Titanium dioxide (E171)1 mg capsule shell

Hypromellose

Red iron oxide (E172)

Yellow iron oxide (E172)

Titanium dioxide (E171)

Shellac (E904)

Propylene glycol (E1520)

Ammonium hydroxide (E527)

Black iron oxide (E172)

Potassium hydroxide (E525)

Not applicable.

4 years.

This medicinal product does not require any special storage conditions.

Talzenna 0.1 mg hard capsules

High-density polyethylene (HDPE) bottle and polypropylene (PP) closure with heat induction sealliner. Pack size: cartons of 30 capsules in a HDPE bottle.

Talzenna 0.25 mg hard capsules

High-density polyethylene (HDPE) bottle and polypropylene (PP) closure with heat induction sealliner. Pack size: cartons of 30 capsules in a HDPE bottle.

Polyvinyl chloride/polyvinylidene chloride (PVC/PVdC) perforated unit dose blister with analuminum peel off foil lidding. Pack sizes: cartons of 30 × 1 capsules, or 60 × 1 capsules, or90 × 1 capsules in unit dose blisters.

Talzenna 1 mg hard capsules

High-density polyethylene (HDPE) bottle and polypropylene (PP) closure with heat induction sealliner. Pack size: cartons of 30 capsules in a HDPE bottle.

Polyvinyl chloride/polyvinylidene chloride (PVC/PVdC) perforated unit dose blister with analuminum peel off foil lidding. Pack size: cartons of 30 × 1 capsules in unit dose blisters.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

Talzenna 0.1 mg hard capsules

EU/1/19/1377/007

Talzenna 0.25 mg hard capsules

EU/1/19/1377/001

EU/1/19/1377/002

EU/1/19/1377/003

EU/1/19/1377/004

Talzenna 1 mg hard capsules

EU/1/19/1377/005

EU/1/19/1377/006

Date of first authorisation: 20 June 2019

Date of latest renewal: 15 April 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.