Talzenna

TALZENNA is indicated as a single agent for the treatment of adult patients with deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated (gBRCAm) human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. Select patients for therapy based on an FDA-authorized companion diagnostic for TALZENNA [see Dosage and Administration (2.1)].

TALZENNA is indicated in combination with enzalutamide for the treatment of adult patients with:

• metastatic androgen pathway modulation-resistant (mAPMR) prostate cancer with homologous recombination repair (HRR) gene mutations, as detected by an FDA-authorized test [see Dosage and Administration (2.1)].
• metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer with HRR gene mutations, as detected by an FDA-authorized test [see Dosage and Administration (2.1)].

gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer

Select 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 mAPMR and mAPMN/S Prostate Cancer

Select patients for the treatment of HRR gene-mutated mAPMR or mAPMN/S prostate cancer 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)].

Information on the FDA-authorized tests for the detection of genetic mutations is available at www.fda.gov/medical-devices/in-vitro-diagnostics/list-fda-authorized-companion-diagnostic-devices-in-vitro-and-imaging-tools.

The recommended dosage of TALZENNA is 1 mg orally once daily, until disease progression or unacceptable toxicity.

The recommended dosage of TALZENNA is 0.5 mg 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 a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had a bilateral orchiectomy.

Take TALZENNA with or without food [see Clinical Pharmacology (12.3)].

Swallow TALZENNA capsules whole. Do not open or dissolve.

If a patient vomits or misses a dose of TALZENNA, instruct them to take the next prescribed dose at the usual time.

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 1 and Table 2. Treatment with TALZENNA should be permanently discontinued if more than 3 dose reductions are required.

gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer

HRR Gene-Mutated mAPMR and mAPMN/S Prostate Cancer

Refer to the enzalutamide prescribing information for dose modifications for adverse reactions associated with enzalutamide.

gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer; HRR Gene-Mutated mAPMR and mAPMN/S Prostate Cancer

Monitor complete blood counts monthly and as clinically indicated [see Warnings and Precautions (5.2)].

gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer

The 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 mAPMR and mAPMN/S Prostate Cancer

The 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)].

gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer

Avoid coadministration of TALZENNA with the following P-glycoprotein (P-gp) inhibitors: itraconazole, amiodarone, carvedilol, clarithromycin, 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 3 – 5 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)].

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including cases with a fatal outcome, has been reported in patients who received TALZENNA.

In clinical studies, among 1,096 patients treated with TALZENNA as a single agent or as part of a combination regimen with enzalutamide, the cumulative incidence of MDS/AML was approximately 1% [see Adverse Reactions (6.1)] including 0.6% with fatal outcomes. The incidence of MDS/AML among patients treated with active control or with placebo in combination with enzalutamide was 0.2%. The median duration of therapy with TALZENNA in patients who developed MDS/AML was approximately 2.8 years (range: 1 to 5.8 years).

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 4 weeks, refer the patient to a hematologist for further investigations including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue TALZENNA.

Myelosuppression consisting of anemia, leukopenia/neutropenia, and/or thrombocytopenia has 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 a single agent. Discontinuation due to anemia, neutropenia, and thrombocytopenia occurred, respectively, in 0.7%, 0.3%, and 0.3% of patients.

Grade ≥3 anemia, neutropenia, and thrombocytopenia were reported, respectively, in 49%, 19%, and 9% of patients receiving TALZENNA in combination with enzalutamide. Forty-one percent of patients required a red blood cell transfusion, including 25% who required more than one transfusion. Discontinuation due to anemia, neutropenia, and thrombocytopenia occurred, respectively, in 7%, 4%, and 1% 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 a hematologist for further investigations including bone marrow analysis and blood sample for cytogenetics [see Dosage and Administration (2.5)].

Based on its mechanism of action and findings from animal data, TALZENNA can cause fetal harm when administered to a 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 1 mg daily. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 7 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 4 months following the last dose of TALZENNA [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 among the 286 patients enrolled in the EMBRACA trial, TALZENNA 0.5 mg daily with enzalutamide in 511 patients enrolled in the TALAPRO-2 trial that included 197 patients with HRR gene-mutated mAPMR prostate cancer, and TALZENNA 0.5 mg daily with enzalutamide in 299 patients with HRR gene-mutated mAPMN/S prostate cancer enrolled in the TALAPRO-3 trial. Among the 810 patients with prostate cancer, 68% were exposed for greater than 1 year, 52% were exposed for greater than 2 years, and 35% were exposed for greater than 3 years. In this safety population, the most common (≥20%) adverse reactions including laboratory abnormalities were decreased hemoglobin (86%), decreased neutrophils (68%), decreased lymphocytes (62%), decreased platelets (54%), fatigue (48%), decreased albumin (26%), decreased calcium (26%), back pain (24%), decreased appetite (22%), and nausea (21%).

gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer
EMBRACA
The safety of TALZENNA as a single agent was evaluated in gBRCAm patients with HER2-negative locally advanced or metastatic breast cancer who had previously received no more than 3 lines of chemotherapy for the treatment of locally advanced/metastatic disease [see Clinical Studies (14.1)]. EMBRACA was a randomized, open-label, multi-center study in which 412 patients received either TALZENNA 1 mg once daily (N=286) or a chemotherapy agent (capecitabine, eribulin, gemcitabine, or vinorelbine) of the healthcare provider's 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 decreased hemoglobin, decreased neutrophils, decreased lymphocytes, decreased platelets, fatigue, increased glucose, increased aspartate aminotransferase (AST), increased alkaline phosphatase (ALP), increased alanine aminotransferase (ALT), decreased calcium, nausea, headache, vomiting, alopecia, diarrhea, and decreased appetite.

Table 5 and Table 6 summarize the most common adverse reactions and laboratory abnormalities, respectively, in patients treated with TALZENNA or chemotherapy in the EMBRACA study.

Clinically 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%).

HRR Gene-Mutated Prostate Cancer

TALAPRO-2 for mAPMR Prostate Cancer

The safety of TALZENNA in combination with enzalutamide was evaluated in patients with HRR gene-mutated mAPMR prostate cancer 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.

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 that resulted in dose interruption of TALZENNA were anemia (42%), neutropenia (15%), thrombocytopenia (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%), neutropenia (15%), thrombocytopenia (6%), and fatigue (4%).

Table 7 and Table 8 summarize the most common adverse reactions and laboratory abnormalities, respectively, in the TALAPRO-2 study.

Clinically 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%).

TALAPRO-3 for mAPMN/S Prostate Cancer

The safety of TALZENNA in combination with enzalutamide was evaluated in patients with HRR gene-mutated mAPMN/S prostate cancer enrolled in TALAPRO-3 [see Clinical Studies (14.2)]. Patients were randomized to receive either TALZENNA 0.5 mg with enzalutamide 160 mg once daily (n=299), or placebo with enzalutamide 160 mg once daily (n=295) until disease progression or unacceptable toxicity.

Serious adverse reactions of TALZENNA in combination with enzalutamide occurred in 42% of patients. Serious adverse reactions reported in >2% of patients included anemia (14%), thrombocytopenia (3%), and urinary tract infection (2%). Fatal adverse reactions occurred in 3% of patients, including cardiac arrest, death, general physical health deterioration, idiopathic pulmonary fibrosis, pancytopenia, and second primary malignancy (1 patient each).

Permanent discontinuation of TALZENNA due to adverse reactions occurred in 19% of patients. The most common adverse reactions that resulted in permanent discontinuation of TALZENNA were neutropenia (6%), anemia (5%), thrombocytopenia and fatigue (2% each), MDS/AML, dizziness, leukopenia, dyspnea, nausea, second primary malignancy, and spinal cord compression (1% each).

Dosage interruption of TALZENNA due to adverse reactions occurred in 69% of patients. The most common adverse reactions that resulted in dosage interruption of TALZENNA were anemia (42%), neutropenia (17%), thrombocytopenia (12%), fatigue (11%), and COVID-19 (5%).

Dose reduction of TALZENNA due to adverse reactions occurred in 60% of patients. The most common adverse reactions that resulted in dose reduction of TALZENNA were anemia (45%), neutropenia (15%), thrombocytopenia and fatigue (6% each).

Table 9 and Table 10 summarize the most common adverse reactions and laboratory abnormalities, respectively, in the TALAPRO-3 study.

Clinically relevant adverse reactions in <10% of patients who received TALZENNA in combination with enzalutamide included headache (6%), vomiting (5%), alopecia (4%), dyspepsia (4%), second primary malignancies (3%), venous thromboembolism (2%), and stomatitis (2%).

Effect of P-gp Inhibitors

Breast Cancer

Avoid coadministration of TALZENNA with the following P-gp inhibitors: itraconazole, amiodarone, carvedilol, clarithromycin, and verapamil. If coadministration of TALZENNA with these P-gp inhibitors cannot be avoided, reduce the dose of TALZENNA [see Dosage and Administration (2.7)]. When the P-gp inhibitor is discontinued, increase the dose of TALZENNA [see Dosage and Administration (2.7)].

Coadministration of TALZENNA with these P-gp inhibitors increased talazoparib concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions.

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)].

HRR Gene-Mutated mAPMR and mAPMN/S Prostate Cancer

The effect of coadministration of P-gp inhibitors on talazoparib exposure when TALZENNA is taken with enzalutamide has not been studied. Monitor patients for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with a P-gp inhibitor [see Dosage and Administration (2.5)].

Effect of Breast Cancer Resistance Protein (BCRP) Inhibitors

Monitor patients for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with a BCRP inhibitor [see Dosage and Administration (2.5)].

Coadministration of TALZENNA with BCRP inhibitors may increase talazoparib exposure [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions.

Risk Summary

Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], TALZENNA can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on TALZENNA use in pregnant women to inform a 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 1 mg daily (see Data). Apprise pregnant women and females of reproductive potential of the potential risk to a 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.

Data

Animal Data

In 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 1 mg daily). A 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.

Risk Summary

There 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 a breastfed child from talazoparib, advise lactating women not to breastfeed during treatment with TALZENNA and for 1 month after the last dose.

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 7 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 4 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)].

The safety and effectiveness of TALZENNA have not been established in pediatric patients.

In clinical trials of TALZENNA enrolling 494 patients with advanced solid tumors who received TALZENNA 1 mg daily as a single agent, 85 (17%) patients were ≥65 years of age, and this included 19 (4%) patients who were ≥75 years old. There were 5 patients ≥85 years old. No overall differences in safety or effectiveness of TALZENNA were observed between patients ≥65 years of age and younger patients.

In clinical trials of TALZENNA enrolling 810 patients who received TALZENNA in combination with enzalutamide, 624 (77%) patients were ≥65 years of age, including 262 (32%) patients who were ≥75 years old. Grade 3 to 5 adverse reactions (91% vs 75%), permanent discontinuations (31% vs 14%), dosage interruptions (75% vs 63%), and dose reductions (65% vs 53%) occurred more frequently in patients ≥75 years of age than in patients <75 years of age. The differences in Grade 3 to 5 adverse reactions between patients ≥75 years of age and patients <75 years of age were primarily driven by an increased incidence of myelosuppression. No overall differences in effectiveness of TALZENNA were observed between patients ≥75 years of age and patients <75 years of age.

No dosage modification is recommended for patients with hepatic impairment [see Clinical Pharmacology (12.3)].

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 (2.6) ]. 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.

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.

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).

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 4.0 ng/mL (43% to 49%).

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 6.5 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, 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 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 (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 azithromycin, atorvastatin, diltiazem, felodipine, fluvoxamine, and quercetin) had no clinically significant effect on talazoparib pharmacokinetics.

Effect of P-gp Inducers: Coadministration of a P-gp inducer (rifampin) with a single 1 mg dose of TALZENNA increased talazoparib C_max 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 2 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 Studies
Transporters: Talazoparib is a substrate of P-gp and BCRP transporters, but not a 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).

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.

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 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 vs 1, 2, or 3), by triple-negative disease status [triple-negative breast cancer (TNBC) vs non-TNBC], and history of central nervous system (CNS) metastasis (yes vs 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 gBRCAm 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% vs 2% were males, 67% vs 75% were White; 11% vs 11% were Asian, and 4% vs 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 11, and the Kaplan-Meier curves for PFS are shown in Figure 1 and final overall survival (OS) in Figure 2.

Figure 1. Kaplan-Meier Curves of PFS – EMBRACA Study

Abbreviation: PFS=progression-free survival.

Figure 1

Figure 2. Kaplan-Meier Curves of OS – EMBRACA Study (ITT Population)

Abbreviations: ITT=intent-to-treat; OS=overall survival.

Figure 2

mAPMR Prostate Cancer

TALAPRO-2

The efficacy of TALZENNA with enzalutamide was evaluated in TALAPRO-2 (NCT03395197), a randomized, double-blind, placebo-controlled, multi-cohort trial in which 399 patients with HRR gene-mutated (HRRm) mAPMR prostate cancer 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 tests. Patients were required to have a 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 a GnRH analog or had had a prior bilateral orchiectomy and needed to have progressed on prior androgen deprivation therapy. Prior treatment with a CYP17 inhibitor or docetaxel for mAPMN/S prostate cancer was permitted. Randomization was stratified by previous treatment with a 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 0 (62%) or 1 (38%). Thirty-nine percent of patients had bone-only disease; 15% had visceral disease. In the mAPMN/S prostate cancer setting, 29% of patients had received docetaxel and 9% had received a 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 blinded independent central review (BICR). An additional efficacy outcome measure was overall survival (OS).

Statistically significant improvements in rPFS and OS were demonstrated in patients randomized to TALZENNA with enzalutamide compared with placebo with enzalutamide. Efficacy results are presented in Table 12, and Figures 3 and 4.

Figure 3. Kaplan-Meier Curves of rPFS - TALAPRO-2 (HRRm mAPMR Prostate Cancer)

Figure 3

Figure 4. Kaplan-Meier Curves of OS – TALAPRO-2 (HRRm mAPMR Prostate Cancer)

Exploratory subgroup analyses of rPFS and OS for patients with BRCA-mutated (BRCAm) and non-BRCAm HRRm are presented in Table 13.

mAPMN/S Prostate Cancer

TALAPRO-3

The efficacy of TALZENNA in combination with enzalutamide was evaluated in TALAPRO-3 (NCT04821622), a randomized, double-blind, placebo-controlled, trial in which 599 patients with HRRm mAPMN/S prostate cancer 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 ctDNA-based next generation sequencing tests. Patients were required to have a 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 a GnRH analog, or had a prior bilateral orchiectomy. Patients must have initiated androgen deprivation therapy or undergone a bilateral orchiectomy in the mAPMN/S prostate cancer setting up to 3 months prior to randomization with or without an androgen receptor pathway inhibitor (ARPI) but were not allowed to have received prior docetaxel. Randomization was stratified by de novo mAPMN/S vs relapsed mAPMN/S prostate cancer, high vs low volume disease, and BRCA vs non-BRCA mutational status.

The median age was 70 years (range: 44 to 89); 100% were male; 57% were White, 39% Asian, 2% Black, 1% Other, 2% unknown/not reported; 10% were Hispanic/Latino, 87% were Not Hispanic or Latino, 3% unknown/not reported; and baseline ECOG performance status was 0 (68%) or 1 (32%). Thirteen percent of patients had received a prior ARPI in the mAPMN/S setting. There were 398 (66%) and 438 (73%) patients with high volume disease and de novo mAPMN/S prostate cancer, respectively, and 307 (51%) with both de novo and high-volume disease. The most commonly mutated HRR genes (>5%), including co-occurring mutations, were: BRCA2 (30%), ATM (28%), CDK12 (19%), CHEK2 (15%) and ATR (7%).

The major efficacy outcome measure was rPFS evaluated according to RECIST, version 1.1 and PCWG3 (bone) criteria, assessed by investigator. An additional efficacy outcome measure was OS.

A statistically significant improvement in rPFS was demonstrated in patients randomized to TALZENNA with enzalutamide compared with those randomized to placebo with enzalutamide. At the time of the rPFS analysis, OS data were immature with 28% deaths in the overall population. Efficacy results are presented in Table 14 and Figure 5.

Figure 5. Kaplan-Meier Curves of rPFS - TALAPRO-3 (HRRm mAPMN/S Prostate Cancer)

Figure 5

Exploratory subgroup analyses of rPFS for patients with BRCAm and non-BRCAm HRRm are presented in Table 15.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature].