Talzenna talazoparib .25 mg Capsule, Liquid Filled, 30-count — NDC 0069-0353-30 (Billing 00069-0353-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Talazoparib is an inhibitor of PARP enzymes, including PARP1 and PARP2, which play a 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 .

12.2Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of TALZENNA have not been fully characterized. Cardiac Electrophysiology At a dose of 1 mg (the recommended dosage for treatment of breast cancer), TALZENNA had no large QTc prolongation (i.e., >20 ms).

12.3Pharmacokinetics After administration of TALZENNA 1 mg orally once daily as a single agent (the recommended dosage for breast cancer), the mean [% coefficient of variation (CV%)] AUC and maximum observed plasma concentration (C max ) of talazoparib at steady-state was 173 (32%) ng.hr/mL and 19 (32%) ng/mL, respectively. The mean (CV%) steady-state C trough 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 C trough ranged from 3.3 to 3.7 ng/mL (45% to 48%).

The pharmacokinetics (PK) of talazoparib is linear from 0.025 mg to 2 mg (2 times the recommended dose for breast cancer). The median accumulation ratio of talazoparib following 1 mg orally once daily is 2.3 to 5.2. Talazoparib plasma concentrations reached steady-state within 2 to 3 weeks when administered as a single agent and within 9 weeks when coadministered with enzalutamide.

Absorption The median time to C max (T max ) was approximately 1 hour (range: 0.4 to 4 hours) after dosing. Food Effect Following administration of a TALZENNA 1 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 C max was decreased by 42%, the median T max was delayed from 1 to 4 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

6.5L/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, 9 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 m 2 ) 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 m 2 ) renal impairment and 163% in patients with severe (eGFR 15 – 29 mL/min/1.73 m 2 ) renal impairment relative to subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m 2 ). Talazoparib stead… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Talazoparib is an inhibitor of PARP enzymes, including PARP1 and PARP2, which play a 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 .

12.3Pharmacokinetics After administration of TALZENNA 1 mg orally once daily as a single agent (the recommended dosage for breast cancer), the mean [% coefficient of variation (CV%)] AUC and maximum observed plasma concentration (C max ) of talazoparib at steady-state was 173 (32%) ng.hr/mL and 19 (32%) ng/mL, respectively. The mean (CV%) steady-state C trough 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 C trough ranged from 3.3 to 3.7 ng/mL (45% to 48%).

The pharmacokinetics (PK) of talazoparib is linear from 0.025 mg to 2 mg (2 times the recommended dose for breast cancer). The median accumulation ratio of talazoparib following 1 mg orally once daily is 2.3 to 5.2. Talazoparib plasma concentrations reached steady-state within 2 to 3 weeks when administered as a single agent and within 9 weeks when coadministered with enzalutamide.

Absorption The median time to C max (T max ) was approximately 1 hour (range: 0.4 to 4 hours) after dosing. Food Effect Following administration of a TALZENNA 1 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 C max was decreased by 42%, the median T max was delayed from 1 to 4 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

6.5L/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, 9 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 m 2 ) 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 m 2 ) renal impairment and 163% in patients with severe (eGFR 15 – 29 mL/min/1.73 m 2 ) renal impairment relative to subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m 2 ). Talazoparib steady-state peak concentration (C max ) 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 a relationship between the protein binding of talazoparib and renal function.

Drug Interaction Studies Clinical Studies Effect of P-gp Inhibitors: Coadministration of a P-gp inhibitor (itraconazole) with a single 0.5 mg dose of TALZENNA increased talazoparib AUC and C max 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 azith… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of TALZENNA have not been fully characterized. Cardiac Electrophysiology At a dose of 1 mg (the recommended dosage for treatment of breast cancer), TALZENNA had no large QTc prolongation (i.e., >20 ms).

14 CLINICAL STUDIES

14.1Deleterious 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 g BRCA m HER2-negative locally advanced or metastatic breast cancer were randomized 2:1 to receive TALZENNA 1 mg or healthcare provider's 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 3 prior cytotoxic chemotherapy regimens for their metastatic or locally advanced disease. Patients were required to have received treatment with an anthracycline and/or a 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 1 of the 4 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 a PARP inhibitor was permitted. Of the 431 patients randomized in the EMBRACA study, 408 (95%) were centrally confirmed to have a deleterious or suspected deleterious g BRCA m using a clinical trial assay; out of which 354 (82%) were confirmed using the BRACAnalysis CDx ® .

BRCA mutation status [breast cancer susceptibility gene 1 ( BRCA1 )-positive or breast cancer susceptibility gene 2 ( 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 0 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 a 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). A statistically significant improvement in PFS was demonstrated for TALZENNA compared to chemotherapy. A 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 Kapla… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with talazoparib. Talazoparib was clastogenic in an in vitro chromosomal aberration assay in human peripheral blood lymphocytes and in an in vivo bone marrow micronucleus assay in rats. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of talazoparib, indicating the potential for genotoxicity in humans.

Talazoparib was not mutagenic in a bacterial reverse mutation (Ames) test. Fertility studies in animals have not been conducted with talazoparib. In repeat-dose toxicity studies up to 3-months duration, talazoparib-related findings in the testis and epididymis at doses ≥0.04 mg/kg/day in rats and ≥0.01 mg/kg/day in dogs included decreased organ weights, luminal cellular debris, reduced sperm, and degeneration/atrophy.

These doses in rats and dogs resulted in approximately 1.0 times and 0.2 times, respectively, the exposure (AUC) in humans at the recommended dose of 1 mg daily. Follicular atresia of the ovary was observed in rats at doses ≥1 mg/kg/day talazoparib, approximately 9.5 times the AUC in patients at the recommended dose of 1 mg daily.