ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:oMyelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1)]oMyelosuppression [see Warnings and Precautions (5.2)]. oMyelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1)]. oMyelosuppression [see Warnings and Precautions (5.2)]. Most common adverse reactions (>=20%) as single agent, including laboratory abnormalities, are:oHemoglobin decreased, neutrophils decreased, lymphocytes decreased, platelets decreased, fatigue, glucose increased, aspartate aminotransferase increased, alkaline phosphatase increased, alanine aminotransferase increased, calcium decreased, nausea, headache, vomiting, alopecia, diarrhea, and decreased appetite. (6.1)Most common adverse reactions (>=10%) in combination with enzalutamide, including laboratory abnormalities, are:oHemoglobin decreased, neutrophils decreased, lymphocytes decreased, fatigue, platelets decreased, calcium decreased, nausea, decreased appetite, sodium decreased, phosphate decreased, fractures, magnesium decreased, dizziness, bilirubin increased, potassium decreased, and dysgeusia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oHemoglobin decreased, neutrophils decreased, lymphocytes decreased, platelets decreased, fatigue, glucose increased, aspartate aminotransferase increased, alkaline phosphatase increased, alanine aminotransferase increased, calcium decreased, nausea, headache, vomiting, alopecia, diarrhea, and decreased appetite. (6.1). oHemoglobin decreased, neutrophils decreased, lymphocytes decreased, fatigue, platelets decreased, calcium decreased, nausea, decreased appetite, sodium decreased, phosphate decreased, fractures, magnesium decreased, dizziness, bilirubin increased, potassium decreased, and dysgeusia. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to single agent TALZENNA in solid tumor clinical studies, including 286 patients enrolled in EMBRACA trial and to TALZENNA 0.5 mg daily with enzalutamide in 511 patients enrolled in the TALAPRO-2 trial that included 197 patients with HRR gene-mutated mCRPC.gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer EMBRACA The safety of TALZENNA as single agent was evaluated in gBRCAm patients with HER2-negative locally advanced or metastatic breast cancer who had previously received no more than lines of chemotherapy for the treatment of locally advanced/metastatic disease [see Clinical Studies (14.1)]. EMBRACA was randomized, open-label, multi-center study in which 412 patients received either TALZENNA mg once daily (N=286) or chemotherapy agent (capecitabine, eribulin, gemcitabine, or vinorelbine) of the healthcare providers choice (N=126) until disease progression or unacceptable toxicity. The median duration of study treatment was 6.1 months in patients who received TALZENNA and 3.9 months in patients who received chemotherapy.Serious adverse reactions of TALZENNA occurred in 32% of patients. Serious adverse reactions reported in >2% of patients included anemia (6%) and pyrexia (2%). Fatal adverse reactions occurred in 1% of patients, including cerebral hemorrhage, liver disorder, veno-occlusive liver disease, and worsening neurological symptoms (1 patient each).Permanent discontinuation due to adverse reactions occurred in 5% of TALZENNA patients. Dosing interruptions due to an adverse reaction of any grade occurred in 65% of patients receiving TALZENNA; dose reductions due to any cause occurred in 53% of TALZENNA patients.The most common (>=20%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, neutrophils decreased, lymphocytes decreased, platelets decreased, fatigue, glucose increased, aspartate aminotransferase increased, alkaline phosphatase increased, alanine aminotransferase increased, calcium decreased, nausea, headache, vomiting, alopecia, diarrhea, and decreased appetite.Table and Table summarize the most common adverse reactions and laboratory abnormalities, respectively, in patients treated with TALZENNA or chemotherapy in the EMBRACA study.Table 5. Adverse ReactionsGraded according to NCI CTCAE 4.03. (>=20%) in Patients Receiving TALZENNA in EMBRACAAbbreviation: N=number of patients.Adverse ReactionsTALZENNAN=286 (%)ChemotherapyN=126 (%)Grades 1-4Grade 3Grade 4Grades 1-4Grade 3Grade 4General Disorders and Administration Site ConditionsFatigueIncludes fatigue and asthenia. 62305050Gastrointestinal DisordersNausea490.304720Vomiting25202320Diarrhea22102660Nervous System DisordersHeadache33202210Skin and Subcutaneous Tissue DisordersAlopecia25002800Metabolism and Nutrition DisordersDecreased appetite210.302210Clinically relevant adverse reactions in <20% of patients who received TALZENNA included abdominal pain (19%), dizziness (17%), dysgeusia (10%), dyspepsia (10%), stomatitis (8%), and febrile neutropenia (0.3%).Table 6. Select Laboratory Abnormalities (>=25%) of Patients in EMBRACAAbbreviation: N=number of patients.TALZENNANThis number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.=286 (%)ChemotherapyN=126 (%)ParameterGrades 1-4Grade 3Grade 4Grades 1-4Grade 3Grade 4Hemoglobin decreased903907760Neutrophils decreased68173702117Lymphocytes decreased76170.75380.8Platelets decreased551142920Glucose increasedThis number represents non-fasting glucose. 54205120Aspartate aminotransferase increased37204830Alkaline phosphatase increased36203420Alanine aminotransferase increased33103720Calcium decreased28101600HRR Gene-mutated mCRPCThe safety of TALZENNA with enzalutamide was evaluated in patients with HRR gene-mutated mCRPC enrolled in TALAPRO-2 [see Clinical Studies (14.2)]. Patients were randomized to receive either TALZENNA 0.5 mg with enzalutamide 160 mg once daily (N=197), or placebo with enzalutamide 160 mg once daily (N=199) until disease progression or unacceptable toxicity. Among patients receiving TALZENNA, 86% were exposed for months or longer, 60% were exposed for greater than one year, and 18% were exposed for greater than two years.Serious adverse reactions of TALZENNA with enzalutamide occurred in 30% of patients. Serious adverse reactions reported in >2% of patients included anemia (9%) and fracture (3%). Fatal adverse reactions occurred in 1.5% of patients, including pneumonia, COVID infection, and sepsis (1 patient each).Permanent discontinuation of TALZENNA due to adverse reactions occurred in 10% of patients treated in the TALZENNA with enzalutamide arm. The most common adverse reactions which resulted in permanent discontinuation of TALZENNA were anemia (4%), fatigue, bone fracture, ischemic heart disease, and spinal cord compression (1% each).Dosage interruption of TALZENNA due to adverse reactions occurred in 58% of patients treated in the TALZENNA with enzalutamide arm. The most common adverse reactions which resulted in dose interruption of TALZENNA were anemia (42%), neutropenia (15%), and platelet count decreased (9%) and fatigue (5%).Dose reduction of TALZENNA due to adverse reactions occurred in 52% of patients treated in the TALZENNA with enzalutamide arm. The most common adverse reactions which resulted in dose reduction of TALZENNA were anemia (43%), neutrophil count decreased (15%), platelet count decreased (6%), and fatigue (4%).The most common adverse reactions (>=10%), including laboratory abnormalities, in patients who received TALZENNA with enzalutamide were hemoglobin decreased, neutrophils decreased, lymphocytes decreased, fatigue, platelets decreased, calcium decreased, nausea, decreased appetite, sodium decreased, phosphate decreased, fractures, magnesium decreased, dizziness, bilirubin increased, potassium decreased, and dysgeusia.Table and Table summarize the most common adverse reactions and laboratory abnormalities, respectively, in the TALAPRO-2 study.Table 7. Adverse ReactionsGraded according to NCI CTCAE 4.03. (>=10%) in Patients Receiving TALZENNA (with Difference Between Arms of >=2%) in TALAPRO-2Abbreviation: N=number of patients.TALZENNA with EnzalutamideN=197Placebo with EnzalutamideN=199Grades 1-4%Grade 3%Grade 4%Grades 1-4%Grade 3%Grade 4%FatigueIncludes fatigue and asthenia. 49404010Nausea21201710.5Decreased appetite20101411FracturesFractures include multiple similar terms. 1430101.50DizzinessIncludes dizziness, dizziness postural, vertigo. 131.5091.50DysgeusiaIncludes ageusia, anosmia, dysgeusia. 10004.500Clinically relevant adverse reactions in <10% of patients who received TALZENNA with enzalutamide included abdominal pain (9%), vomiting (9%), alopecia (7%), dyspepsia (4%), venous thromboembolism (3%) and stomatitis (2%).Table 8. Select Laboratory Abnormalities (>=10%) That Worsened from Baseline in Patients Who Received TALZENNA in TALAPRO-2Abbreviation: N=number of patients.Laboratory AbnormalityTALZENNA with EnzalutamideN=197The denominator used to calculate the rate varied from 198 to 199 in the placebo with enzalutamide arm based on the number of patients with baseline value and at least one post-treatment value.Placebo with EnzalutamideN=199Grades 1-4%Grade 3%Grade 4%Grades 1-4%Grade 3%Grade 4%Hemoglobin decreased794103460Neutrophils decreased601811801Lymphocytes decreased581303670Platelets decreased456380.50Calcium decreased25011101Sodium decreased2230201.50Phosphate decreased17311320Magnesium decreased14011200.5Bilirubin increased110.50700Potassium decreased1101710.5.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Talazoparib is an inhibitor of PARP enzymes, including PARP1 and PARP2, which play role in DNA repair. In vitro studies with cancer cell lines that harbored defects in DNA repair genes, including BRCA1 and BRCA2, have shown that talazoparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, decreased cell proliferation, and apoptosis. Talazoparib anti-tumor activity was observed in patient-derived xenograft breast cancer models bearing mutated BRCA1 or mutated BRCA2 or wild type BRCA1 and BRCA2.. 12.2 Pharmacodynamics. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of TALZENNA have not been fully characterized.Cardiac ElectrophysiologyAt dose of mg (the recommended dosage for treatment of breast cancer), TALZENNA had no large QTc prolongation (i.e., >20 ms).. 12.3 Pharmacokinetics. After administration of TALZENNA mg orally once daily as single agent (the recommended dosage for breast cancer), the mean [% coefficient of variation (CV%)] AUC and maximum observed plasma concentration (Cmax) of talazoparib at steady-state was 173 (32%) ng.hr/mL and 19 (32%) ng/mL, respectively. The mean (CV%) steady-state Ctrough was 3.5 (61%) ng/mL.After administration of TALZENNA 0.5 mg orally once daily (the recommended dosage for prostate cancer) with enzalutamide, the mean (CV%) steady-state Ctrough ranged from 3.3 to 3.7 ng/mL (45% to 48%).The pharmacokinetics (PK) of talazoparib is linear from 0.025 mg to mg (2 times the recommended dose for breast cancer). The median accumulation ratio of talazoparib following mg orally once daily is 2.3 to 5.2. Talazoparib plasma concentrations reached steady-state within to weeks when administered as single agent and within weeks when coadministered with enzalutamide.Absorption The median time to Cmax (Tmax) was approximately hour (range: 0.4 to hours) after dosing.Food Effect Following administration of TALZENNA mg dose soft gelatin capsule with high-fat, high-calorie food (approximately 800 to 1,000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), the mean steady-state Cmax was decreased by 42%, the median Tmax was delayed from to hours, and AUC was not affected as compared to those under fasted conditions.Distribution The mean apparent volume of distribution of talazoparib is 420 L. In vitro, protein binding of talazoparib is 74% and is independent of talazoparib concentration.Elimination The mean terminal plasma half-life (+-standard deviation) is 90 (+-58) hours and the mean apparent oral clearance (inter-subject variability) is 6.5 L/h (31%).Metabolism Talazoparib undergoes minimal hepatic metabolism. The identified metabolic pathways include mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluoro-talazoparib, and glucuronide conjugation.Excretion Excretion of talazoparib in urine was the major route of elimination. Approximately 69% (55% unchanged) of the total administered radiolabeled dose of talazoparib was recovered in urine, and 20% (14% unchanged) was recovered in feces.Specific Populations Age (18 to 88 years), sex, race (361 White, 41 Asian, 16 Black, Others, and 63 Not Reported), body weight (36 to 162 kg), and mild to severe hepatic impairment had no clinically significant effect on the PK of talazoparib.Patients with Renal Impairment Mild (eGFR 60 89 mL/min/1.73 m2) renal impairment had no clinically significant effect on talazoparib pharmacokinetics. Talazoparib steady-state total exposure (AUC) increased by 43% in subjects with moderate (eGFR 30 59 mL/min/1.73 m2) renal impairment and 163% in patients with severe (eGFR 15 29 mL/min/1.73 m2) renal impairment relative to subjects with normal renal function (eGFR >= 90 mL/min/1.73 m2). Talazoparib steady-state peak concentration (Cmax) increased by 32% in subjects with moderate renal impairment and 89% in subjects with severe renal impairment, relative to subjects with normal renal function. Similar increases in AUC were observed with talazoparib when given with enzalutamide for patients with moderate and severe renal impairment. The PK of talazoparib has not been studied in patients requiring hemodialysis. There was no evidence of relationship between the protein binding of talazoparib and renal function.Drug Interaction Studies Clinical Studies Effect of P-gp Inhibitors: Coadministration of P-gp inhibitor (itraconazole) with single 0.5 mg dose of TALZENNA increased talazoparib AUC and Cmax by approximately 56% and 40%, respectively. Coadministration with the following other P-gp inhibitors: amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil increased talazoparib exposure by 45%.Coadministration with other P-gp inhibitors (including azithromycin, atorvastatin, diltiazem, felodipine, fluvoxamine, and quercetin) had no clinically significant effect on talazoparib pharmacokinetics.Effect of P-gp Inducers: Coadministration of P-gp inducer (rifampin) with single mg dose of TALZENNA increased talazoparib Cmax by 37% with no effect on talazoparib AUC.Effect of Acid-Reducing Agents: Coadministration of acid-reducing agents including proton pump inhibitors (PPI), histamine receptor antagonists (H2RA), or other acid-reducing agents has no effect on the absorption of talazoparib.Enzalutamide: Coadministration of enzalutamide with TALZENNA increased talazoparib exposure approximately 2-fold.In Vitro StudiesTransporters: Talazoparib is substrate of P-gp and BCRP transporters, but not substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, BSEP, MATE1, or MATE2-K.Talazoparib is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, BSEP, MATE1, or MATE2-K.CYP Enzymes: Talazoparib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5.Talazoparib is not an inducer of CYP1A2, CYP2B6, or CYP3A4.UGT: Talazoparib is not an inhibitor of UGT isoforms (1A1, 1A4, 1A6, 1A9, 2B7, and 2B15).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Deleterious or Suspected Deleterious Germline BRCA-mutated HER2-negative Locally Advanced or Metastatic Breast Cancer EMBRACA (NCT01945775) was an open-label study in which patients (N=431) with gBRCAm HER2-negative locally advanced or metastatic breast cancer were randomized 2:1 to receive TALZENNA mg or healthcare providers choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine) until disease progression or unacceptable toxicity. Randomization was stratified by prior lines of chemotherapy for metastatic disease (0 versus 1, 2, or 3), by triple-negative disease status [triple-negative breast cancer (TNBC) versus non-TNBC], and history of central nervous system (CNS) metastasis (yes versus no).Patients received no more than prior cytotoxic chemotherapy regimens for their metastatic or locally advanced disease. Patients were required to have received treatment with an anthracycline and/or taxane (unless contraindicated) in the neoadjuvant, adjuvant, and/or metastatic treatment setting. First-line treatment for advanced or metastatic disease with no prior adjuvant chemotherapy was allowed if the investigator determined that of the chemotherapy choices in the control arm would be an appropriate treatment option for the patient. Patients with prior platinum therapy for advanced disease were required to have no evidence of disease progression during platinum therapy. No prior treatment with PARP inhibitor was permitted. Of the 431 patients randomized in the EMBRACA study, 408 (95%) were centrally confirmed to have deleterious or suspected deleterious gBRCAm using clinical trial assay; out of which 354 (82%) were confirmed using the BRACAnalysis CDx(R). BRCA mutation status [breast cancer susceptibility gene (BRCA1)-positive or breast cancer susceptibility gene (BRCA2)-positive] was similar across both treatment arms.The median age of patients treated with TALZENNA was 46 years (range 28 to 84) and 51 years (range 24 to 89) among patients treated with chemotherapy. Among all randomized patients, 1% versus 2% were males, 67% versus 75% were White; 11% versus 11% were Asian, and 4% versus 1% were Black or African American in the TALZENNA and chemotherapy arms, respectively. Almost all patients (98%) in both arms had an Eastern Cooperative Oncology Group (ECOG) performance status of or 1. Approximately 56% of patients had estrogen receptor-positive and/or progesterone receptor-positive disease; 44% of patients had triple-negative disease, and the proportions were balanced across both treatment arms. Fifteen percent (15%) of patients in the TALZENNA arm and 14% of patients in the chemotherapy arm had history of CNS metastases. Ninety-one percent (91%) of patients in the TALZENNA arm had received prior taxane therapy, and 85% had received prior anthracycline therapy in any setting. Sixteen percent (16%) of patients in the TALZENNA arm and 21% of patients in the chemotherapy arm had received prior platinum treatment in any setting. The median number of prior cytotoxic regimens for patients with advanced breast cancer was one; 38% received no prior cytotoxic regimens for advanced or metastatic disease, 37% received one, 20% received two, and 5% received three or more prior cytotoxic regimens.The major efficacy outcome measure was progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by blinded independent central review (BICR). statistically significant improvement in PFS was demonstrated for TALZENNA compared to chemotherapy. sensitivity analysis of investigator-assessed PFS was consistent with the BICR-assessed PFS results. Consistent PFS results were observed across patient subgroups defined by study stratification factors (prior lines of chemotherapy, TNBC status, and history of CNS metastases). Efficacy data from the EMBRACA study are summarized in Table 9, and the Kaplan-Meier curves for PFS are shown in Figure and final overall survival (OS) in Figure 2.Table 9. Efficacy Results EMBRACA StudyAbbreviations: BICR=blinded independent central review; CI=confidence interval; DOR=duration of response; ITT=intent-to-treat; N=number of patients; ORR=objective response rate; OS=overall survival; PFS=progression-free survival.TALZENNAChemotherapyPFS by BICRN=287N=144 Disease progression or deaths, (%)186 (65)83 (58) Median months (95% CI)8.6 (7.2, 9.3)5.6 (4.2, 6.7) Hazard ratio (95% CI)Hazard ratio is estimated from Cox proportional hazards model 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], and by history of central nervous system metastasis (yes versus no) and is relative to overall chemotherapy with <1 favoring talazoparib. 0.54 (0.41, 0.71) p-valuep-values (2-sided) from the log-rank test stratified by number of prior cytotoxic chemotherapy regimens, triple-negative status and history of central nervous system metastasis. p<0.0001Patients with Measurable Disease by InvestigatorConducted in ITT population with measurable disease at baseline.N=219N=114 ORR, (95% CI)Response rate based on confirmed responses. 50.2 (43.4, 57.0)18.4 (11.8, 26.8) MedianMedian estimated from Kaplan-Meier probabilities. DOR months (95% CI)6.4 (5.4, 9.5)3.9 (3.0, 7.6)OSN=287N=144 Deaths, (%)216 (75)108 (75) Median months (95% CI)19.3 (16.6, 22.5)19.5 (17.4, 22.4) Hazard ratio (95% CI) 0.85 (0.67, 1.07) p-value p=0.1693Figure 1. Kaplan-Meier Curves of PFS EMBRACA StudyAbbreviation: PFS=progression-free survival.Figure 2. Kaplan-Meier Curves of OS EMBRACA Study (ITT Population)Abbreviations: ITT=intent-to-treat; OS=overall survival.. Figure 1. Figure 2. 14.2 HRR Gene-mutated mCRPC The efficacy of TALZENNA with enzalutamide was evaluated in TALAPRO-2 (NCT03395197), randomized, double-blind, placebo-controlled, multi-cohort trial in which 399 patients with HRR gene-mutated (HRRm) mCRPC were randomized 1:1 to receive enzalutamide 160 mg daily plus either TALZENNA 0.5 mg or placebo daily until unacceptable toxicity or disease progression. Mutation status of HRR genes was determined prospectively using solid tumor tissue or circulating tumor DNA (ctDNA)-based next generation sequencing assays. Patients were required to have mutation in at least one of 12 genes involved directly or indirectly in the HRR pathway (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C). All patients received GnRH analog or had prior bilateral orchiectomy and needed to have progressed on prior androgen deprivation therapy. Prior treatment with CYP17 inhibitor or docetaxel for metastatic castration-sensitive prostate cancer (mCSPC) was permitted. Randomization was stratified by previous treatment with CYP17 inhibitor or docetaxel (yes/no).The median age was 70 years (range: 41 to 90); 100% were male; 68% were White, 21% Asian, 2.8% Black, 0.8% Other, 7% unknown/not reported; 12% were Hispanic/Latino; and baseline ECOG performance status was (62%) or (38%). Thirty-nine percent of patients had bone-only disease; 15% had visceral disease. In the mCSPC setting, 29% percent of patients had received docetaxel and 9% had received prior CYP17 inhibitor. The most commonly mutated HRR genes (>5%), including co-occurring mutations, were: BRCA2 (34%), ATM (22%), CDK12 (19%), CHEK2 (18%), and BRCA1 (6%).The major efficacy outcome measure was radiographic progression-free survival (rPFS) evaluated according to RECIST, version 1.1 and Prostate Cancer Working Group (PCWG3) (bone) criteria, assessed by BICR. An additional efficacy outcome measure was OS.A statistically significant improvement in rPFS and OS were demonstrated in patients randomized to TALZENNA with enzalutamide compared with placebo with enzalutamide. Efficacy results are presented in Table 10, and Figures and 4.Table 10. Efficacy Results TALAPRO-2 (HRR Gene-mutated mCRPC)Abbreviations: BICR=blinded independent central review; CI=confidence interval; CSPC=castration-sensitive prostate cancer; HRR=homologous recombination repair; mCRPC=metastatic castration-resistant prostate cancer; N=number of patients; NR=not reached.TALZENNA with EnzalutamideN=200Placebo with EnzalutamideN=199Radiographic Progression-free Survival (rPFS) by BICR Number of events, (%)66 (33)104 (52) Median months (95% CI)NR (21.9, NR)13.8 (11.0, 16.7) Hazard ratio (95% CI)Hazard ratio and CI are based on Cox PH model stratified by previous treatment for CSPC. 0.45 (0.33, 0.61) p-valuep-value (2-sided) is based on log-rank test stratified by previous treatment for CSPC. p<0.0001 Overall Survival (OS) Deaths, (%)93 (47)126 (63) Median months (95% CI)45.1 (35.4, NR)31.1 (27.3, 35.4) Hazard ratio (95% CI) 0.62 (0.48, 0.81) p-value p=0.0005Figure 3. Kaplan-Meier Curves of rPFS TALAPRO-2 (HRR Gene-mutated mCRPC)Abbreviations: HRR=homologous recombination repair; mCRPC=metastatic castration-resistant prostate cancer; rPFS=radiographic progression-free survival.Figure 4. Kaplan-Meier Curves of OS TALAPRO-2 (HRR Gene-mutated mCRPC)Abbreviations: HRR=homologous recombination repair; mCRPC=metastatic castration-resistant prostate cancer; OS=overall survival.Exploratory subgroup analyses of rPFS and OS for patients with BRCA-mutated (BRCAm) and non-BRCAm HRRm are presented in Table 11.Table 11. Exploratory rPFS and OS Subgroup Analyses by BRCAm Status for TALAPRO-2 (HRR Gene-mutated mCRPC)Abbreviations: BRCAm=breast cancer susceptibility gene-mutated; CI=confidence interval; CSPC=castration-sensitive prostate cancer; HRRm=homologous recombination repair gene-mutated; NR=not reached; rPFS=radiographic progression-free survival.BRCAmNon-BRCAm HRRmIncludes patients who were incorrectly randomized in the HRRm stratum who did not have HRR gene mutations.TALZENNA with EnzalutamideN=71Placebo with EnzalutamideN=84TALZENNA with EnzalutamideN=129Placebo with EnzalutamideN=115rPFSNumber of events, (%)15 (21)54 (64)51 (40)50 (43)Median months (95% CI)NR (NR, NR)11.0 (8.3, 11.1)24.7 (16.4, NR)16.7 (13.8, 27.7)Hazard ratio (95% CI)0.20 (0.11, 0.36)0.74 (0.50, 1.09) Overall Survival (OS)Deaths, (%)30 (42)56 (67)63 (49)70 (61)Median months (95% CI)NR(35.4, NR)28.5(24.5, 34.4)42.4(34.2, NR)32.6(28.0, 42.2)Hazard ratio (95% CI)Hazard ratio and CI are based on Cox PH model unstratified by previous treatment for CSPC. 0.48 (0.31, 0.75)0.71 (0.51, 1.00). Figure 3. Figure 4.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to single agent TALZENNA in solid tumor clinical studies, including 286 patients enrolled in EMBRACA trial and to TALZENNA 0.5 mg daily with enzalutamide in 511 patients enrolled in the TALAPRO-2 trial that included 197 patients with HRR gene-mutated mCRPC.gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer EMBRACA The safety of TALZENNA as single agent was evaluated in gBRCAm patients with HER2-negative locally advanced or metastatic breast cancer who had previously received no more than lines of chemotherapy for the treatment of locally advanced/metastatic disease [see Clinical Studies (14.1)]. EMBRACA was randomized, open-label, multi-center study in which 412 patients received either TALZENNA mg once daily (N=286) or chemotherapy agent (capecitabine, eribulin, gemcitabine, or vinorelbine) of the healthcare providers choice (N=126) until disease progression or unacceptable toxicity. The median duration of study treatment was 6.1 months in patients who received TALZENNA and 3.9 months in patients who received chemotherapy.Serious adverse reactions of TALZENNA occurred in 32% of patients. Serious adverse reactions reported in >2% of patients included anemia (6%) and pyrexia (2%). Fatal adverse reactions occurred in 1% of patients, including cerebral hemorrhage, liver disorder, veno-occlusive liver disease, and worsening neurological symptoms (1 patient each).Permanent discontinuation due to adverse reactions occurred in 5% of TALZENNA patients. Dosing interruptions due to an adverse reaction of any grade occurred in 65% of patients receiving TALZENNA; dose reductions due to any cause occurred in 53% of TALZENNA patients.The most common (>=20%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, neutrophils decreased, lymphocytes decreased, platelets decreased, fatigue, glucose increased, aspartate aminotransferase increased, alkaline phosphatase increased, alanine aminotransferase increased, calcium decreased, nausea, headache, vomiting, alopecia, diarrhea, and decreased appetite.Table and Table summarize the most common adverse reactions and laboratory abnormalities, respectively, in patients treated with TALZENNA or chemotherapy in the EMBRACA study.Table 5. Adverse ReactionsGraded according to NCI CTCAE 4.03. (>=20%) in Patients Receiving TALZENNA in EMBRACAAbbreviation: N=number of patients.Adverse ReactionsTALZENNAN=286 (%)ChemotherapyN=126 (%)Grades 1-4Grade 3Grade 4Grades 1-4Grade 3Grade 4General Disorders and Administration Site ConditionsFatigueIncludes fatigue and asthenia. 62305050Gastrointestinal DisordersNausea490.304720Vomiting25202320Diarrhea22102660Nervous System DisordersHeadache33202210Skin and Subcutaneous Tissue DisordersAlopecia25002800Metabolism and Nutrition DisordersDecreased appetite210.302210Clinically relevant adverse reactions in <20% of patients who received TALZENNA included abdominal pain (19%), dizziness (17%), dysgeusia (10%), dyspepsia (10%), stomatitis (8%), and febrile neutropenia (0.3%).Table 6. Select Laboratory Abnormalities (>=25%) of Patients in EMBRACAAbbreviation: N=number of patients.TALZENNANThis number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.=286 (%)ChemotherapyN=126 (%)ParameterGrades 1-4Grade 3Grade 4Grades 1-4Grade 3Grade 4Hemoglobin decreased903907760Neutrophils decreased68173702117Lymphocytes decreased76170.75380.8Platelets decreased551142920Glucose increasedThis number represents non-fasting glucose. 54205120Aspartate aminotransferase increased37204830Alkaline phosphatase increased36203420Alanine aminotransferase increased33103720Calcium decreased28101600HRR Gene-mutated mCRPCThe safety of TALZENNA with enzalutamide was evaluated in patients with HRR gene-mutated mCRPC enrolled in TALAPRO-2 [see Clinical Studies (14.2)]. Patients were randomized to receive either TALZENNA 0.5 mg with enzalutamide 160 mg once daily (N=197), or placebo with enzalutamide 160 mg once daily (N=199) until disease progression or unacceptable toxicity. Among patients receiving TALZENNA, 86% were exposed for months or longer, 60% were exposed for greater than one year, and 18% were exposed for greater than two years.Serious adverse reactions of TALZENNA with enzalutamide occurred in 30% of patients. Serious adverse reactions reported in >2% of patients included anemia (9%) and fracture (3%). Fatal adverse reactions occurred in 1.5% of patients, including pneumonia, COVID infection, and sepsis (1 patient each).Permanent discontinuation of TALZENNA due to adverse reactions occurred in 10% of patients treated in the TALZENNA with enzalutamide arm. The most common adverse reactions which resulted in permanent discontinuation of TALZENNA were anemia (4%), fatigue, bone fracture, ischemic heart disease, and spinal cord compression (1% each).Dosage interruption of TALZENNA due to adverse reactions occurred in 58% of patients treated in the TALZENNA with enzalutamide arm. The most common adverse reactions which resulted in dose interruption of TALZENNA were anemia (42%), neutropenia (15%), and platelet count decreased (9%) and fatigue (5%).Dose reduction of TALZENNA due to adverse reactions occurred in 52% of patients treated in the TALZENNA with enzalutamide arm. The most common adverse reactions which resulted in dose reduction of TALZENNA were anemia (43%), neutrophil count decreased (15%), platelet count decreased (6%), and fatigue (4%).The most common adverse reactions (>=10%), including laboratory abnormalities, in patients who received TALZENNA with enzalutamide were hemoglobin decreased, neutrophils decreased, lymphocytes decreased, fatigue, platelets decreased, calcium decreased, nausea, decreased appetite, sodium decreased, phosphate decreased, fractures, magnesium decreased, dizziness, bilirubin increased, potassium decreased, and dysgeusia.Table and Table summarize the most common adverse reactions and laboratory abnormalities, respectively, in the TALAPRO-2 study.Table 7. Adverse ReactionsGraded according to NCI CTCAE 4.03. (>=10%) in Patients Receiving TALZENNA (with Difference Between Arms of >=2%) in TALAPRO-2Abbreviation: N=number of patients.TALZENNA with EnzalutamideN=197Placebo with EnzalutamideN=199Grades 1-4%Grade 3%Grade 4%Grades 1-4%Grade 3%Grade 4%FatigueIncludes fatigue and asthenia. 49404010Nausea21201710.5Decreased appetite20101411FracturesFractures include multiple similar terms. 1430101.50DizzinessIncludes dizziness, dizziness postural, vertigo. 131.5091.50DysgeusiaIncludes ageusia, anosmia, dysgeusia. 10004.500Clinically relevant adverse reactions in <10% of patients who received TALZENNA with enzalutamide included abdominal pain (9%), vomiting (9%), alopecia (7%), dyspepsia (4%), venous thromboembolism (3%) and stomatitis (2%).Table 8. Select Laboratory Abnormalities (>=10%) That Worsened from Baseline in Patients Who Received TALZENNA in TALAPRO-2Abbreviation: N=number of patients.Laboratory AbnormalityTALZENNA with EnzalutamideN=197The denominator used to calculate the rate varied from 198 to 199 in the placebo with enzalutamide arm based on the number of patients with baseline value and at least one post-treatment value.Placebo with EnzalutamideN=199Grades 1-4%Grade 3%Grade 4%Grades 1-4%Grade 3%Grade 4%Hemoglobin decreased794103460Neutrophils decreased601811801Lymphocytes decreased581303670Platelets decreased456380.50Calcium decreased25011101Sodium decreased2230201.50Phosphate decreased17311320Magnesium decreased14011200.5Bilirubin increased110.50700Potassium decreased1101710.5.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oTake TALZENNA with or without food. (2.4)Breast CanceroThe recommended dosage of TALZENNA is mg taken orally once daily until disease progression or unacceptable toxicity. (2.2)oFor adverse reactions, consider dosing interruption or dose reduction. (2.5)HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC)oThe recommended dosage of TALZENNA is 0.5 mg taken orally once daily with enzalutamide until disease progression or unacceptable toxicity. (2.3)oPatients should also receive gonadotropic-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. (2.3). oTake TALZENNA with or without food. (2.4). oThe recommended dosage of TALZENNA is mg taken orally once daily until disease progression or unacceptable toxicity. (2.2). oFor adverse reactions, consider dosing interruption or dose reduction. (2.5). oThe recommended dosage of TALZENNA is 0.5 mg taken orally once daily with enzalutamide until disease progression or unacceptable toxicity. (2.3). oPatients should also receive gonadotropic-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. (2.3). 2.1 Patient Selection. Information on the FDA-approved tests for the detection of genetic mutations is available at http://www.fda.gov/companiondiagnostics.gBRCAm HER2-negative Locally Advanced or Metastatic Breast CancerSelect patients for the treatment of advanced breast cancer with TALZENNA based on the presence of germline BRCA mutations [see Indications and Usage (1.1), Clinical Studies (14.1)].HRR Gene-mutated Metastatic Castration-Resistant Prostate CancerSelect patients for the treatment of HRR gene-mutated mCRPC with TALZENNA based on the presence of alterations in genes directly or indirectly involved in HRR (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) [see Indications and Usage (1.2), Clinical Studies (14.2)].An FDA-approved test for the detection of HRR gene mutations for use with TALZENNA is not currently available.. 2.2 Recommended Dosage for gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer. The recommended dosage of TALZENNA is mg taken orally once daily, until disease progression or unacceptable toxicity.. 2.3 Recommended Dosage for HRR Gene-mutated mCRPC The recommended dosage of TALZENNA is 0.5 mg taken orally once daily with enzalutamide until disease progression or unacceptable toxicity.Refer to the enzalutamide prescribing information for recommended enzalutamide dosing information.Patients receiving TALZENNA and enzalutamide should also receive gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.. 2.4 Administration Take TALZENNA with or without food.Swallow TALZENNA capsules whole. Do not open or dissolve.If patient vomits or misses dose of TALZENNA, instruct them to take the next prescribed dose at the usual time.. 2.5 Dosage Modifications for Adverse Reactions. To manage adverse reactions, consider interruption of treatment with or without dose reduction based on severity and clinical presentation. Recommended dose reductions are indicated in Table and Table 2. Treatment with TALZENNA should be discontinued if more than dose reductions are required.gBRCAm HER2-negative Locally Advanced or Metastatic Breast CancerTable 1. Dose Reduction Levels for Adverse Reactions--Breast CancerDose ReductionsDose LevelRecommended starting dose1 mg once dailyFirst dose reduction0.75 mg once dailySecond dose reduction0.5 mg once dailyThird dose reduction0.25 mg once dailyHRR Gene-mutated mCRPCTable 2. Dose Reduction Levels for Adverse Reactions--mCRPCDose ReductionsDose LevelRecommended starting dose0.5 mg once dailyFirst dose reduction0.35 mg once dailySecond dose reduction0.25 mg once dailyThird dose reduction0.1 mg once dailyRefer to the enzalutamide prescribing information for dose modifications for adverse reactions associated with enzalutamide.gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer and HRR Gene-mutated mCRPCMonitor complete blood counts monthly and as clinically indicated [see Warnings and Precautions (5.2)].Table 3. Dose Modification and Management for Adverse ReactionsAdverse ReactionsWithhold TALZENNA Until Levels Resolve toResume TALZENNAHemoglobin <8 g/dL>=9 g/dLResume TALZENNA at reduced dosePlatelet count <50,000/uL>=75,000/uLNeutrophil count <1,000/uL>=1500/uLNon-hematologic Grade or Grade 4<=Grade 1Consider resuming TALZENNA at reduced dose or discontinue. 2.6 Recommended Dosage in Patients with Renal Impairment. gBRCAm HER2-negative Locally Advanced or Metastatic Breast CancerThe recommended dosage of TALZENNA for patients with moderate renal impairment (CLcr 30 59 mL/min) is 0.75 mg taken orally once daily [see Use in Specific Populations (8.7)].The recommended dosage of TALZENNA for patients with severe renal impairment (CLcr 15 29 mL/min) is 0.5 mg taken orally once daily [see Use in Specific Populations (8.7)].HRR Gene-mutated mCRPCThe recommended dosage of TALZENNA for patients with moderate renal impairment (CLcr 30 59 mL/min) is 0.35 mg taken orally once daily with enzalutamide [see Use in Specific Populations (8.7)].The recommended dosage of TALZENNA for patients with severe renal impairment (CLcr 15 29 mL/min) is 0.25 mg taken orally once daily with enzalutamide [see Use in Specific Populations (8.7)].. 2.7 Dosage Modifications for P-glycoprotein Inhibitors. gBRCAm HER2-negative Locally Advanced or Metastatic Breast CancerAvoid coadministration of TALZENNA with the following P-glycoprotein (P-gp) inhibitors: itraconazole, amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil. If coadministration of TALZENNA with these P-gp inhibitors cannot be avoided, reduce the dose of TALZENNA to 0.75 mg taken orally once daily. When the P-gp inhibitor is discontinued, increase the dose of TALZENNA (after - half-lives of the P-gp inhibitor) to the dose of TALZENNA that was used before starting the P-gp inhibitor [see Drug Interactions (7.1)].Monitor for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with other P-gp inhibitors [see Dosage and Administration (2.5)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).oMDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or need for blood transfusions. This may be sign of hematological toxicity or more serious uncommon bone marrow problem called MDS or AML, which have been reported in patients who received PARP inhibitors [see Warnings and Precautions (5.1)].oMyelosuppression: Advise patients that TALZENNA may affect hematopoiesis and can cause anemia, leukopenia/neutropenia, and/or thrombocytopenia [see Warnings and Precautions (5.2)].oAdministration Instructions: Advise patients that TALZENNA can be taken once daily with or without food. Instruct patients that if they miss dose of TALZENNA, they should take their next normal dose at the usual time. Also advise patients to swallow each capsule whole, and that capsules must not be opened or dissolved [see Dosage and Administration (2.4)].oEmbryo-Fetal Toxicity: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with TALZENNA and for months after the last dose. Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for months after receiving the last dose of TALZENNA [see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)].oLactation: Advise patients not to breastfeed while taking TALZENNA and for month after receiving the last dose [see Use in Specific Populations (8.2)].. oMDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or need for blood transfusions. This may be sign of hematological toxicity or more serious uncommon bone marrow problem called MDS or AML, which have been reported in patients who received PARP inhibitors [see Warnings and Precautions (5.1)].. oMyelosuppression: Advise patients that TALZENNA may affect hematopoiesis and can cause anemia, leukopenia/neutropenia, and/or thrombocytopenia [see Warnings and Precautions (5.2)].. oAdministration Instructions: Advise patients that TALZENNA can be taken once daily with or without food. Instruct patients that if they miss dose of TALZENNA, they should take their next normal dose at the usual time. Also advise patients to swallow each capsule whole, and that capsules must not be opened or dissolved [see Dosage and Administration (2.4)].. oEmbryo-Fetal Toxicity: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with TALZENNA and for months after the last dose. Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for months after receiving the last dose of TALZENNA [see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)].. oLactation: Advise patients not to breastfeed while taking TALZENNA and for month after receiving the last dose [see Use in Specific Populations (8.2)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. After administration of TALZENNA mg orally once daily as single agent (the recommended dosage for breast cancer), the mean [% coefficient of variation (CV%)] AUC and maximum observed plasma concentration (Cmax) of talazoparib at steady-state was 173 (32%) ng.hr/mL and 19 (32%) ng/mL, respectively. The mean (CV%) steady-state Ctrough was 3.5 (61%) ng/mL.After administration of TALZENNA 0.5 mg orally once daily (the recommended dosage for prostate cancer) with enzalutamide, the mean (CV%) steady-state Ctrough ranged from 3.3 to 3.7 ng/mL (45% to 48%).The pharmacokinetics (PK) of talazoparib is linear from 0.025 mg to mg (2 times the recommended dose for breast cancer). The median accumulation ratio of talazoparib following mg orally once daily is 2.3 to 5.2. Talazoparib plasma concentrations reached steady-state within to weeks when administered as single agent and within weeks when coadministered with enzalutamide.Absorption The median time to Cmax (Tmax) was approximately hour (range: 0.4 to hours) after dosing.Food Effect Following administration of TALZENNA mg dose soft gelatin capsule with high-fat, high-calorie food (approximately 800 to 1,000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), the mean steady-state Cmax was decreased by 42%, the median Tmax was delayed from to hours, and AUC was not affected as compared to those under fasted conditions.Distribution The mean apparent volume of distribution of talazoparib is 420 L. In vitro, protein binding of talazoparib is 74% and is independent of talazoparib concentration.Elimination The mean terminal plasma half-life (+-standard deviation) is 90 (+-58) hours and the mean apparent oral clearance (inter-subject variability) is 6.5 L/h (31%).Metabolism Talazoparib undergoes minimal hepatic metabolism. The identified metabolic pathways include mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluoro-talazoparib, and glucuronide conjugation.Excretion Excretion of talazoparib in urine was the major route of elimination. Approximately 69% (55% unchanged) of the total administered radiolabeled dose of talazoparib was recovered in urine, and 20% (14% unchanged) was recovered in feces.Specific Populations Age (18 to 88 years), sex, race (361 White, 41 Asian, 16 Black, Others, and 63 Not Reported), body weight (36 to 162 kg), and mild to severe hepatic impairment had no clinically significant effect on the PK of talazoparib.Patients with Renal Impairment Mild (eGFR 60 89 mL/min/1.73 m2) renal impairment had no clinically significant effect on talazoparib pharmacokinetics. Talazoparib steady-state total exposure (AUC) increased by 43% in subjects with moderate (eGFR 30 59 mL/min/1.73 m2) renal impairment and 163% in patients with severe (eGFR 15 29 mL/min/1.73 m2) renal impairment relative to subjects with normal renal function (eGFR >= 90 mL/min/1.73 m2). Talazoparib steady-state peak concentration (Cmax) increased by 32% in subjects with moderate renal impairment and 89% in subjects with severe renal impairment, relative to subjects with normal renal function. Similar increases in AUC were observed with talazoparib when given with enzalutamide for patients with moderate and severe renal impairment. The PK of talazoparib has not been studied in patients requiring hemodialysis. There was no evidence of relationship between the protein binding of talazoparib and renal function.Drug Interaction Studies Clinical Studies Effect of P-gp Inhibitors: Coadministration of P-gp inhibitor (itraconazole) with single 0.5 mg dose of TALZENNA increased talazoparib AUC and Cmax by approximately 56% and 40%, respectively. Coadministration with the following other P-gp inhibitors: amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil increased talazoparib exposure by 45%.Coadministration with other P-gp inhibitors (including azithromycin, atorvastatin, diltiazem, felodipine, fluvoxamine, and quercetin) had no clinically significant effect on talazoparib pharmacokinetics.Effect of P-gp Inducers: Coadministration of P-gp inducer (rifampin) with single mg dose of TALZENNA increased talazoparib Cmax by 37% with no effect on talazoparib AUC.Effect of Acid-Reducing Agents: Coadministration of acid-reducing agents including proton pump inhibitors (PPI), histamine receptor antagonists (H2RA), or other acid-reducing agents has no effect on the absorption of talazoparib.Enzalutamide: Coadministration of enzalutamide with TALZENNA increased talazoparib exposure approximately 2-fold.In Vitro StudiesTransporters: Talazoparib is substrate of P-gp and BCRP transporters, but not substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, BSEP, MATE1, or MATE2-K.Talazoparib is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, BSEP, MATE1, or MATE2-K.CYP Enzymes: Talazoparib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5.Talazoparib is not an inducer of CYP1A2, CYP2B6, or CYP3A4.UGT: Talazoparib is not an inhibitor of UGT isoforms (1A1, 1A4, 1A6, 1A9, 2B7, and 2B15).

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 6/2025PATIENT INFORMATIONTALZENNA(R) (Tal-ZEN-ah)(talazoparib)capsulesWhat is the most important information should know about TALZENNATALZENNA may cause serious side effects, including:oBone marrow problems called Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML). Some people who have cancer and who have received previous treatment with chemotherapy or certain other medicines for their cancer have developed MDS or AML during or after treatment with TALZENNA. MDS or AML may lead to death. If you develop MDS or AML, your healthcare provider will stop treatment with TALZENNA.Symptoms of low blood cell counts are common during treatment with TALZENNA, but can be sign of serious problems, including MDS or AML. Tell your healthcare provider if you have any of the following symptoms during treatment with TALZENNA: weakness weight loss fever frequent infections blood in urine or stool shortness of breath feeling very tired bruising or bleeding more easily Your healthcare provider will do blood tests to check your blood cell counts: every month during treatment with TALZENNA. weekly if you have low blood cell counts that last long time.Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with TALZENNA if you get certain side effects.See What are the possible side effects of TALZENNA below for other side effects of TALZENNA.What is TALZENNATALZENNA is prescription medicine used:oalone to treat adults with human epidermal growth factor receptor (HER2)-negative breast cancer:owho have certain type of an abnormal inherited BRCA gene, and owhose cancer has spread to other parts of the body (locally advanced or metastatic). Your healthcare provider will perform test to make sure that TALZENNA is right for you.oin combination with medicine called enzalutamide, to treat adults with prostate cancerowith certain abnormal inherited or acquired genes called homologous recombination repair (HRR genes) andowhich no longer responds to hormone therapy or surgical treatment to lower testosterone and has spread to other parts of the body (metastatic). Your healthcare provider will perform test to make sure that TALZENNA is right for you.It is not known if TALZENNA is safe and effective in children.Before taking TALZENNA, tell your healthcare provider about all of your medical conditions, including if you:ohave kidney problems.oare pregnant or plan to become pregnant. TALZENNA can harm your unborn baby and may cause loss of pregnancy (miscarriage). You should not become pregnant during treatment with TALZENNA. Females who are able to become pregnant:oYour healthcare provider may do pregnancy test before you start treatment with TALZENNA.oYou should use effective birth control (contraception) during treatment with TALZENNA and for months after the last dose of TALZENNA. Talk to your healthcare provider about forms of birth control that may be right for you.oTell your healthcare provider right away if you are pregnant or think you are pregnant during treatment with TALZENNA. Males with female partners who are pregnant or are able to become pregnant:oYou should use effective birth control during treatment with TALZENNA and for months after the last dose of TALZENNA.oare breastfeeding or plan to breastfeed. It is not known if TALZENNA passes into your breast milk. Do not breastfeed during treatment with TALZENNA and for month after the last dose of TALZENNA. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking TALZENNA with certain other medicines can affect how TALZENNA works and may cause side effects.Know the medicines you take. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine. How should take TALZENNAoTake TALZENNA exactly as your healthcare provider tells you.oDo not change your dose or stop taking TALZENNA without first talking with your healthcare provider.oIf you are prescribed TALZENNA for breast cancer, take TALZENNA time day.oIf you are prescribed TALZENNA for prostate cancer:oTake TALZENNA with enzalutamide time day.oYou should start or continue gonadotropin-releasing hormone (GnRH) analog therapy during your treatment with TALZENNA and enzalutamide unless you have had surgery to lower the amount of testosterone in your body (surgical castration).oTake TALZENNA with or without food.oSwallow TALZENNA capsules whole. Do not dissolve or open TALZENNA capsules.oIf you vomit or miss dose of TALZENNA, take your next dose at your regular time. Do not take an extra dose to make up for missed dose.What are the possible side effects of TALZENNATALZENNA may cause serious side effects, including:oSee What is the most important information should know about TALZENNAThe most common side effects of TALZENNA when taken alone include:odecreased red blood cell countsodecreased white blood cell countsotiredness or weaknessodecreased platelet countsoincreased blood sugar levelsoincreased liver function testsonauseaoheadacheodecreased blood calcium levelsovomitingohair lossodiarrheaodecreased appetiteThe most common side effects of TALZENNA when taken in combination with enzalutamide include:odecreased red blood cell countsodecreased white blood cell countsotiredness or weaknessodecreased platelet countsodecreased calcium in the bloodonauseaodecreased appetiteodecreased sodium in the bloododecreased phosphate in the bloodobone injuriesodecreased magnesium in the bloododizzinessoincreased bilirubin in the bloododecreased potassium in the bloodochanges in your sense of tasteTALZENNA may cause fertility problems in males. This may affect your ability to father child. Talk to your healthcare provider if this is concern for you.These are not all of the possible side effects of TALZENNA.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store TALZENNAoStore TALZENNA at 68F to 77F (20C to 25C).Keep TALZENNA and all medicines out of the reach of children. General information about the safe and effective use of TALZENNA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use TALZENNA for condition for which it is not prescribed. Do not give TALZENNA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about TALZENNA that is written for health professionals. What are the ingredients in TALZENNAActive ingredient: talazoparib tosylate Inactive ingredients: gelatin, glycerol, iron oxide (red), iron oxide (yellow), polyethylene glycol 400, purified water, sorbitol, titanium dioxide, and tocopherol For more information, go to www.pfizer.com or call 1-800-438-1985.LAB-1562-2.0. oBone marrow problems called Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML). Some people who have cancer and who have received previous treatment with chemotherapy or certain other medicines for their cancer have developed MDS or AML during or after treatment with TALZENNA. MDS or AML may lead to death. If you develop MDS or AML, your healthcare provider will stop treatment with TALZENNA.Symptoms of low blood cell counts are common during treatment with TALZENNA, but can be sign of serious problems, including MDS or AML. Tell your healthcare provider if you have any of the following symptoms during treatment with TALZENNA:. Your healthcare provider will do blood tests to check your blood cell counts:. oalone to treat adults with human epidermal growth factor receptor (HER2)-negative breast cancer:owho have certain type of an abnormal inherited BRCA gene, and owhose cancer has spread to other parts of the body (locally advanced or metastatic).. owho have certain type of an abnormal inherited BRCA gene, and owhose cancer has spread to other parts of the body (locally advanced or metastatic).. Your healthcare provider will perform test to make sure that TALZENNA is right for you.. oin combination with medicine called enzalutamide, to treat adults with prostate cancerowith certain abnormal inherited or acquired genes called homologous recombination repair (HRR genes) andowhich no longer responds to hormone therapy or surgical treatment to lower testosterone and has spread to other parts of the body (metastatic).. owith certain abnormal inherited or acquired genes called homologous recombination repair (HRR genes) and. owhich no longer responds to hormone therapy or surgical treatment to lower testosterone and has spread to other parts of the body (metastatic).. Your healthcare provider will perform test to make sure that TALZENNA is right for you.. ohave kidney problems.. oare pregnant or plan to become pregnant. TALZENNA can harm your unborn baby and may cause loss of pregnancy (miscarriage). You should not become pregnant during treatment with TALZENNA.. Females who are able to become pregnant:oYour healthcare provider may do pregnancy test before you start treatment with TALZENNA.oYou should use effective birth control (contraception) during treatment with TALZENNA and for months after the last dose of TALZENNA. Talk to your healthcare provider about forms of birth control that may be right for you.oTell your healthcare provider right away if you are pregnant or think you are pregnant during treatment with TALZENNA.. oYour healthcare provider may do pregnancy test before you start treatment with TALZENNA.. oYou should use effective birth control (contraception) during treatment with TALZENNA and for months after the last dose of TALZENNA. Talk to your healthcare provider about forms of birth control that may be right for you.. oTell your healthcare provider right away if you are pregnant or think you are pregnant during treatment with TALZENNA.. Males with female partners who are pregnant or are able to become pregnant:oYou should use effective birth control during treatment with TALZENNA and for months after the last dose of TALZENNA.. oYou should use effective birth control during treatment with TALZENNA and for months after the last dose of TALZENNA.. oare breastfeeding or plan to breastfeed. It is not known if TALZENNA passes into your breast milk. Do not breastfeed during treatment with TALZENNA and for month after the last dose of TALZENNA. Talk to your healthcare provider about the best way to feed your baby during this time.. oTake TALZENNA exactly as your healthcare provider tells you.. oDo not change your dose or stop taking TALZENNA without first talking with your healthcare provider.. oIf you are prescribed TALZENNA for breast cancer, take TALZENNA time day.. oIf you are prescribed TALZENNA for prostate cancer:oTake TALZENNA with enzalutamide time day.oYou should start or continue gonadotropin-releasing hormone (GnRH) analog therapy during your treatment with TALZENNA and enzalutamide unless you have had surgery to lower the amount of testosterone in your body (surgical castration).. oTake TALZENNA with enzalutamide time day.. oYou should start or continue gonadotropin-releasing hormone (GnRH) analog therapy during your treatment with TALZENNA and enzalutamide unless you have had surgery to lower the amount of testosterone in your body (surgical castration).. oTake TALZENNA with or without food.. oSwallow TALZENNA capsules whole. Do not dissolve or open TALZENNA capsules.. oIf you vomit or miss dose of TALZENNA, take your next dose at your regular time. Do not take an extra dose to make up for missed dose.. oSee What is the most important information should know about TALZENNA. odecreased red blood cell counts. odecreased white blood cell counts. otiredness or weakness. odecreased platelet counts. oincreased blood sugar levels. oincreased liver function tests. onausea. oheadache. odecreased blood calcium levels. ovomiting. ohair loss. odiarrhea. odecreased appetite. odecreased red blood cell counts. odecreased white blood cell counts. otiredness or weakness. odecreased platelet counts. odecreased calcium in the blood. onausea. odecreased appetite. odecreased sodium in the blood. odecreased phosphate in the blood. obone injuries. odecreased magnesium in the blood. odizziness. oincreased bilirubin in the blood. odecreased potassium in the blood. ochanges in your sense of taste. oStore TALZENNA at 68F to 77F (20C to 25C).. Logo.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oLactation: Advise women not to breastfeed. (8.2)oRenal Impairment: Reduce the dose and monitor for increased adverse reactions for patients with moderate or severe renal impairment. (2.6, 8.7). oLactation: Advise women not to breastfeed. (8.2). oRenal Impairment: Reduce the dose and monitor for increased adverse reactions for patients with moderate or severe renal impairment. (2.6, 8.7). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], TALZENNA can cause embryo-fetal harm when administered to pregnant woman. There are no available data on TALZENNA use in pregnant women to inform drug-associated risk. In an animal reproduction study, the administration of talazoparib to pregnant rats during the period of organogenesis caused fetal malformations and structural skeletal variations and embryo-fetal death at maternal exposures that were 0.24 times the AUC in patients receiving the recommended dose of mg daily (see Data). Apprise pregnant women and females of reproductive potential of the potential risk to fetus.The background risk of major birth defects and miscarriage for the indicated population is unknown. In the general U.S. population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.DataAnimal DataIn an embryo-fetal development toxicity study, pregnant rats received oral doses of 0.015, 0.05, and 0.15 mg/kg/day talazoparib during the period of organogenesis. Talazoparib caused embryo-fetal death at doses >=0.015 mg/kg/day (approximately 0.24 times the AUC in patients at the recommended dose of mg daily). dose of 0.015 mg/kg/day caused decreased fetal body weights and an increased incidence of fetal malformations (depressed eye bulge, small eye, split sternebra, and fused cervical vertebral arch) and structural variations including misshapen or incomplete ossification of the sternebra, skull, rib, and vertebra.. 8.2 Lactation. Risk SummaryThere are no data on the presence of talazoparib in human milk, the effects of the drug on milk production, or the effects of the drug on the breastfed child. Because of the potential for serious adverse reactions in breastfed child from talazoparib, advise lactating women not to breastfeed during treatment with TALZENNA and for month after the last dose.. 8.3 Females and Males of Reproductive Potential. TALZENNA can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating TALZENNA treatment.Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for months following the last dose of TALZENNA.Males Based on genotoxicity and animal reproduction studies, advise male patients with female partners of reproductive potential and pregnant partners to use effective contraception during treatment with TALZENNA and for months following the last dose [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)].Infertility Males Based on animal studies, TALZENNA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of TALZENNA have not been established in pediatric patients.. 8.5 Geriatric Use. In clinical trials of TALZENNA enrolling 494 patients with advanced solid tumors who received TALZENNA mg daily as single agent, 85 (17%) patients were >=65 years of age, and this included 19 (4%) patients who were >=75 years old. There were patients >=85 years old. In the TALAPRO-2 trial, of 197 patients who received TALZENNA, 77% were >=65 years of age, while 30% were >=75 years of age. No overall differences in safety or effectiveness of TALZENNA were observed between these patients and younger patients.. 8.6 Hepatic Impairment. No dosage modification is recommended for patients with hepatic impairment [see Clinical Pharmacology (12.3)].. 8.7 Renal Impairment. Reduce the recommended dosage of TALZENNA in patients with moderate (CLcr 30 59 mL/min) and severe (CLcr 15 29 mL/min) renal impairment [see Dosage and Administration (2.7)]. Monitor patients with severe renal impairment for increased adverse reactions and modify the dosage as recommended for adverse reactions [see Dosage and Administration (2.5)].No dose adjustment is recommended for patients with mild renal impairment (CLcr 60 89 mL/min). TALZENNA has not been studied in patients requiring hemodialysis.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oMyelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): MDS/AML occurred in patients exposed to TALZENNA, and some cases were fatal. Monitor patients for hematological toxicity and discontinue if MDS/AML is confirmed. (5.1)oMyelosuppression: TALZENNA may affect hematopoiesis and can cause anemia, neutropenia, and/or thrombocytopenia. (5.2)oEmbryo-Fetal Toxicity: TALZENNA can cause fetal harm. Advise of the potential risk to the fetus and to use effective contraception. (5.3, 8.1, 8.3). oMyelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): MDS/AML occurred in patients exposed to TALZENNA, and some cases were fatal. Monitor patients for hematological toxicity and discontinue if MDS/AML is confirmed. (5.1). oMyelosuppression: TALZENNA may affect hematopoiesis and can cause anemia, neutropenia, and/or thrombocytopenia. (5.2). oEmbryo-Fetal Toxicity: TALZENNA can cause fetal harm. Advise of the potential risk to the fetus and to use effective contraception. (5.3, 8.1, 8.3). 5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia. Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including cases with fatal outcome, has been reported in patients who received TALZENNA.Overall, MDS/AML has been reported in 0.4% (3 out of 788) of solid tumor patients treated with TALZENNA as single agent in clinical studies. In TALAPRO-2, MDS/AML occurred in out of 511 (0.4%) patients treated with TALZENNA and enzalutamide and in out of 517 (0%) patients treated with placebo and enzalutamide [see Adverse Reactions (6.1)]. The durations of TALZENNA treatment in these patients prior to developing MDS/AML were 0.3, 1, 2, 3, and years. Most of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy.Do not start TALZENNA until patients have adequately recovered from hematological toxicity caused by previous chemotherapy. Monitor blood counts monthly during treatment with TALZENNA. For prolonged hematological toxicities, interrupt TALZENNA and monitor blood counts weekly until recovery. If counts do not recover within weeks, refer the patient to hematologist for further investigations including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue TALZENNA.. 5.2 Myelosuppression Myelosuppression consisting of anemia, neutropenia, and/or thrombocytopenia, have been reported in patients treated with TALZENNA [see Adverse Reactions (6.1)].Grade >=3 anemia, neutropenia, and thrombocytopenia were reported, respectively, in 39%, 21%, and 15% of patients receiving TALZENNA as single agent. Discontinuation due to anemia, neutropenia, and thrombocytopenia occurred, respectively, in 0.7%, 0.3%, and 0.3% of patients.In TALAPRO-2, Grade >=3 anemia, neutropenia, and thrombocytopenia were reported, respectively, in 48%, 19%, and 9% of patients receiving TALZENNA and enzalutamide. Forty-two percent of patients (216/511) required red blood cell transfusion, including 25% (127/511) who required more than one transfusion. Discontinuation due to anemia, neutropenia, and thrombocytopenia occurred, respectively, in 8%, 3%, and 0.4% of patients.Withhold TALZENNA until patients have adequately recovered from hematological toxicity caused by previous therapy. Monitor blood counts monthly during treatment with TALZENNA. If hematological toxicities do not resolve within 28 days, discontinue TALZENNA and refer the patient to hematologist for further investigations including bone marrow analysis and blood sample for cytogenetics [see Dosage and Administration (2.5)].. 5.3 Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal data, TALZENNA can cause fetal harm when administered to pregnant woman. In an animal reproduction study, administration of talazoparib to pregnant rats during the period of organogenesis caused fetal malformations and structural skeletal variations, and embryo-fetal death at exposures that were 0.24 times the area under the concentration-time curve (AUC) in patients receiving the recommended human dose of mg daily. Apprise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment and for months following the last dose of TALZENNA [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for months following the last dose of TALZENNA [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].