Talazoparib Tosylate (Monograph)

Brand name: Talzenna [Web]
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Oct 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; a potent and selective inhibitor of polyadenosine diphosphate [ADP]-ribose polymerase (PARP).

Uses for Talazoparib Tosylate

Breast Cancer

Single-agent therapy for the treatment of confirmed or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated (as detected by an FDA-approved companion diagnostic test [BRACAnalysis CDx]), human epidermal growth factor receptor type 2 (HER2)-negative locally advanced or metastatic breast cancer.

Guidelines generally recommend talazoparib for treatment of patients with germline BRCA-mutated, HER2-negative metastatic breast cancer in place of chemotherapy in patients who are no longer benefiting from endocrine therapy.

Prostate Cancer

In combination with enzalutamide for the treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).

Clinicians should select patients for talazoparib therapy 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). An FDA-approved test for the detection of HRR gene mutation for use with talazoparib is not currently available.

According to a joint guideline from the American Urological Association (AUA) and the Society of Urologic Oncology (SUO), clinicians should offer newly diagnosed mCRPC patients androgen deprivation therapy with abiraterone plus prednisone, docetaxel, or enzalutamide. The choice of initial treatment should be driven by adverse effect profile and prior treatment regimens.

Guideline also states that PARP inhibitors, such as talazoparib, should be offered to patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC following prior treatment with enzalutamide or abiraterone acetate, and/or a taxane-based chemotherapy.

Talazoparib Tosylate Dosage and Administration

General

Pretreatment Screening

Confirmation of the diagnosis of deleterious germline breast cancer susceptibility gene (BRCA)-mutated locally advanced or metastatic breast cancer by an FDA-approved companion diagnostic test is necessary for selecting patients for talazoparib therapy.
Monitor CBC counts prior to initiating treatment with talazoparib.
Verify pregnancy status in females of reproductive potential.

Patient Monitoring

Monitor CBC counts monthly and as clinically indicated.

Administration

Oral Administration

Administer orally once daily without regard to meals.

Swallow capsules whole; do not dissolve or open. If dose is vomited or missed, do not take an additional dose; take the next dose at the usual time.

Dosage

Available as talazoparib tosylate; dosage expressed in terms of talazoparib.

Adults

Breast Cancer

Oral

1 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Avoid concomitant use of potent inhibitors of P-gp; if concomitant use cannot be avoided, reduce talazoparib dosage from 1 mg once daily to 0.75 mg once daily. If concomitant use of the P-gp inhibitor is discontinued, return the talazoparib dosage to the dosage used prior to P-gp inhibitor initiation.

Monitor for increased toxicity and modify the talazoparib dosage regimen as recommended for adverse reactions when talazoparib is coadministered with other P-gp inhibitors.

Prostate Cancer

Oral

0.5 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or have undergone a bilateral orchiectomy.

Dosage Modifications

Oral

If adverse reactions occur, consider interruption of therapy or dosage reduction based on severity and clinical presentation.

Breast Cancer: If dosage reduction is necessary, reduce dosage to 0.75 mg once daily.

If dosage reduction from 0.75 mg once daily is necessary, reduce dosage to 0.5 mg once daily.

If further reduction is necessary, reduce dosage to 0.25 mg once daily.

Permanently discontinue drug if 0.25 mg once daily is not tolerated.

Prostate Cancer: If dosage reduction is necessary, reduce dosage to 0.35 mg once daily.

If dosage reduction from 0.35 mg once daily is necessary, reduce dosage to 0.25 mg once daily.

If further reduction is necessary, reduce dosage to 0.1 mg once daily.

Permanently discontinue drug if 0.1 mg once daily is not tolerated.

Dosage Modification for Hematologic Toxicity

Oral

For anemia (hemoglobin concentrations <8 g/dL), interrupt talazoparib therapy until hemoglobin concentrations ≥9 g/dL, and then resume at a reduced dosage.

For thrombocytopenia (platelet count <50,000/mm³), interrupt talazoparib therapy until platelet count ≥75,000/mm³, and then resume at a reduced dosage.

For neutropenia (ANC <1000/mm³), interrupt talazoparib therapy until ANC ≥1500/mm³, and then resume at a reduced dosage.

If MDS or AML is confirmed, discontinue talazoparib therapy.

Dosage Modification for Nonhematologic Effects

Oral

If grade 3 or 4 nonhematologic toxicity occurs, interrupt talazoparib therapy until the toxicity resolves to grade 1 or less, and then consider dosage reduction or discontinuance of therapy.

Special Populations

Hepatic Impairment

No dosage adjustment required for mild, moderate, or severe hepatic impairment.

Renal Impairment

Breast Cancer: Mild renal impairment (Cl_cr 60–89 mL/minute): Dosage adjustment not necessary.

Moderate renal impairment (Cl_cr 30–59 mL/minute): Reduce initial dosage to 0.75 mg once daily.

Severe renal impairment (Cl_cr 15-29 mL/minute): Reduce initial dosage to 0.5 mg once daily.

Prostate Cancer: Mild renal impairment (Cl_cr 60–89 mL/minute): Dosage adjustment not necessary.

Moderate renal impairment (Cl_cr 30–59 mL/minute): Reduce initial dosage to 0.35 mg once daily.

Severe renal impairment (Clcr 15-29 mL/minute): Reduce initial dosage to 0.25 mg once daily.

Dialysis:No specific dosage recommendations at this time for either indication.

Geriatric Use

No specific dosage recommendations at this time.

Cautions for Talazoparib Tosylate

Contraindications

None.

Warnings/Precautions

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML)

MDS and AML reported rarely in patients receiving talazoparib. The majority of patients with MDS/AML had received previous chemotherapy with platinum-containing agents and/or other DNA-damaging antineoplastic agents.

Monitor CBC counts at baseline and monthly thereafter. Delay initiation of talazoparib until hematologic toxicity caused by previous chemotherapy has adequately resolved.

If prolonged hematologic toxicity occurs, interrupt therapy and monitor CBC counts weekly until recovery. If hematologic toxicity persists for >4 weeks following interruption of therapy, refer patient to a hematologist for further evaluation, including bone marrow analysis and cytogenetic testing of a blood sample. If MDS/AML is confirmed, discontinue talazoparib.

Myelosuppression

Adverse hematologic effects (e.g., anemia, neutropenia, thrombocytopenia) may occur.

Delay initiation of talazoparib until hematologic toxicity caused by previous chemotherapy has adequately resolved. Monitor CBC counts at baseline and monthly thereafter. If hematologic toxicity occurs, temporary interruption, dosage reduction, or discontinuance of talazoparib may be necessary.

If hematologic toxicity develops and persists for >4 weeks following interruption of therapy, refer patient to a hematologist for further evaluation, including bone marrow analysis and cytogenetic testing of a blood sample.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal findings; embryotoxicity and teratogenicity demonstrated in animals.

Confirmation of pregnancy status recommended prior to initiating talazoparib therapy. Avoid pregnancy during therapy. Females of reproductive potential should use effective contraceptive methods while receiving talazoparib and for ≥7 months after the drug is discontinued. Males who are partners with such females, including males partners of pregnant females, should use effective contraceptive methods while receiving the drug and for ≥4 months after the drug is discontinued. Apprise patients of potential fetal hazard if the drug is used during pregnancy.

Specific Populations

Pregnancy

May cause fetal harm.

Confirm pregnancy status prior to initiation of therapy.

Lactation

Not known whether talazoparib is distributed into milk. Discontinue nursing during therapy and for ≥1 month after drug discontinuance.

Females and Males of Reprodutive Potential

Animal studies suggest impairment of male fertility. The effect on fertility in humans is not known.

Confirm pregnancy status prior to initiation of talazoparib therapy. Advise females of reproductive potential to use effective contraceptive methods during talazoparib therapy and for ≥7 months after discontinuance of the drug. Advise males who are partners of such females, including male partners of pregnant females, to use effective methods of contraception while receiving the drug and for ≥4 months after the drug is discontinued.

Pediatric Use

Safety and efficacy not established.

Pharmacokinetic profile not established in patients <18 years of age.

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.

Hepatic Impairment

Pharmacokinetics not altered by mild to severe hepatic impairment; dosage adjustment not necessary in such patients.

Renal Impairment

Increased systemic exposure in patients with mild, moderate, or severe renal impairment; dosage reduction recommended in patients with moderate or severe renal impairment.

Not studied in patients receiving dialysis.

Common Adverse Effects

Adverse effects reported in ≥20% of patients receiving talazoparib as a single agent include decreased hemoglobin; decreased neutrophils, lymphocytes, and platelets; fatigue; increased glucose; increased AST, ALT, and alkaline phosphatase; decreased calcium; nausea; headache; alopecia, vomiting; diarrhea; and decreased appetite.

Adverse effects reported in ≥10% of patients receiving talazoparib in combination with enzalutamide include decreased hemoglobin; decreased neutrophils, lymphocytes, and platelets; fatigue; decreased calcium, sodium, magnesium, potassium, and phosphate; nausea; decreased appetite; fractures; dizziness; increased bilirubin; and dysgeusia.

Drug Interactions

In vitro, does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 or induce CYP isoenzymes 1A2, 2B6, or 3A4.

In vitro, talazoparib is not an inhibitor of UGT 1A1, 1A4, 1A6, 1A9, 2B7, and 2B15.

In vitro, talazoparib is a substrate, but not an inhibitor, of P-gp and breast cancer resistance protein (BCRP). In vitro, talazoparib is not a substrate or inhibitor of organic anion transport protein (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, bile salt export pump (BSEP), and multidrug and toxic compound extrusion protein (MATE) 1 and MATE2K.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Because talazoparib undergoes minimal hepatic metabolism, pharmacokinetic interactions appear unlikely with inhibitors or inducers of CYP isoenzymes.

Drugs Affecting Efflux Transport Systems

Potent P-gp inhibitors: Potential increased systemic exposure of talazoparib.

Breast Cancer: Avoid concomitant use. If concomitant therapy cannot be avoided, reduce talazoparib dosage from 1 mg once daily to 0.75 mg once daily. If potent P-gp inhibitor is discontinued, resume talazoparib (after 3–5 terminal half-lives of the P-gp inhibitor) at dosage used prior to initiation of P-gp inhibitor.

Moderate or weak P-gp inhibitors: No clinically meaningful effect on systemic exposure of talazoparib. Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur.

Prostate Cancer:Effect of concurent use of P-gp inhibitors on talazoparib exposure when talazoparib is taken in combination with enzalutamide not evaluated.

Monitor for increased adverse reactions and potentially modify talazoparib dosage regimen.

BCRP inhibitors: Potential increased systemic exposure of talazoparib. If concomitant use cannot be avoided, monitor for signs of toxicity and modify the talazoparib dosage regimen.

Specific Drugs

Drug	Interaction	Comments
Amiodarone	Potent P-gp inhibitors (e.g., amiodarone): Increased systemic exposure of talazoparib by approximately 45%	Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage If amiodarone discontinued, resume talazoparib (after 3–5 terminal half-lives of amiodarone) at dosage used prior to initiation of amiodarone
Antacids	No clinically meaningful effect on talazoparib absorption
Atorvastatin	Moderate/weak P-gp inhibitors (e.g., atorvastatin): No clinically meaningful effect on systemic exposure of talazoparib	Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur
Calcium-channel blocking agents (e.g., diltiazem, felodipine, verapamil)	Potent P-gp inhibitors (e.g., verapamil): Increased systemic exposure of talazoparib by approximately 45% Moderate/weak P-gp inhibitors (e.g., diltiazem, felodipine): No clinically meaningful effect on systemic exposure of talazoparib	Potent P-gp inhibitors: Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage If potent P-gp inhibitor discontinued, resume talazoparib (after 3–5 terminal half-lives of the P-gp inhibitor) at dosage used prior to initiation of P-gp inhibitor Moderate/weak P-gp inhibitors: Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur
Carvedilol	Potent P-gp inhibitors (e.g., carvedilol): Increased systemic exposure of talazoparib by approximately 45%	Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage If carvedilol discontinued, resume talazoparib (after 3–5 terminal half-lives of carvedilol) at dosage used prior to initiation of carvedilol
Fluvoxamine	Moderate/weak P-gp inhibitors (e.g., fluvoxamine): No clinically meaningful effect on systemic exposure of talazoparib	Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur
Histamine H₂-receptor antagonists	No clinically meaningful effect on talazoparib absorption
Itraconazole	Potent P-gp inhibitors (e.g., itraconazole): Increased systemic exposure of talazoparib by approximately 56%	Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage If itraconazole discontinued, resume talazoparib (after 3–5 terminal half-lives of itraconazole) at dosage used prior to initiation of itraconazole
Macrolides (azithromycin, clarithromycin)	Potent P-gp inhibitors (e.g., clarithromycin): Increased systemic exposure of talazoparib by approximately 45% Moderate/weak P-gp inhibitors (e.g., azithromycin): No clinically meaningful effect on systemic exposure of talazoparib	Potent P-gp inhibitors: Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage If potent P-gp inhibitor discontinued, resume talazoparib (after 3–5 terminal half-lives of the P-gp inhibitor) at dosage used prior to initiation of P-gp inhibitor Moderate/weak P-gp inhibitors: Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur
Proton-pump inhibitors	No clinically meaningful effect on talazoparib absorption
Rifampin	Increassed peak serum levels of talazoparib by approximately 37% with no effect on systemic exposure.

Talazoparib Tosylate Pharmacokinetics

Absorption

Bioavailability

Pharmacokinetics are linear over a dosage range of 0.025–2 mg; median accumulation ratio is 2.3–5.2 following repeated administration of talazoparib 1 mg daily.

Median time to peak plasma concentrations is 1–2 hours following oral administration.

Steady-state concentrations are achieved within 2–3 weeks.

Food

Administration with a high-fat, high-calorie meal (800–1000 calories with approximately 50–75% of calories from fat) delayed the time to peak concentrations by 1-4 hours and decreased mean peak plasma concentrations by 46%, but did not substantially affect the extent of absorption.

Special Populations

Mild to severe hepatic impairment does not affect pharmacokinetics of talazoparib.

Dialysis: Pharmacokinetics not studied.

Age, body weight, sex, or race does not affect pharmacokinetics of talazoparib.

Distribution

Extent

Not known whether talazoparib is distributed into milk.

Plasma Protein Binding

74% (independent of talazoparib concentration).

Elimination

Metabolism

Minimal hepatic metabolism.

Mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluorotalazoparib, and glucuronide conjugation.

Elimination Route

Eliminated in urine (68.7%; 54.6% as unchanged drug) and feces (19.7%; 13.6% as unchanged drug).

Half-life

Mean terminal half-life: 90 hours.

Special Populations

In patients with mild (Cl_cr 60–89 mL/minute), moderate (Cl_cr 30–59 mL/minute), or severe (Cl_cr 15-29 mL/minute) renal impairment, systemic exposure increased by 12, 43, and 163%, respectively, and peak plasma concentration increased by 11, 32, and 89%, respectively, relative to individuals with normal renal function.

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted between 15–30°C).

Actions

Potent and selective inhibitor of mammalian PARP enzymes, including PARP-1 and PARP-2. PARP enzymes are involved in normal cellular homeostasis, including DNA transcription, cell cycle regulation, and DNA repair.
Talazoparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, which result in DNA damage, decreased cell proliferation, and apoptosis.
PARP inhibitors, including talazoparib, appear to be selective for tumors cells harboring certain homologous recombination deficiencies (e.g., BRCA1 and BRCA2 mutations).
In vitro, ≥18-fold or 37-fold more potent than rucaparib and olaparib in BRCA-deficient or phosphatase and tensin homolog (PTEN)-deficient tumor cells lines, respectively.
Substantially more potent than rucaparib and olaparib in estrogen receptor-negative, progesterone receptor-negative, and HER2-negative breast tumor cell lines harboring BRCA1 mutation.
Exhibits antitumor activity of xenograft models of human cancer harboring either mutated or wild-type BRCA1/2.

Advice to Patients

Advise patients to take talazoparib capsules once daily without regard to meals. Advise patients to swallow talazoparib capsules whole and not to dissolve or open the capsules.
If a dose is missed or vomited, administer the next dose at the regularly scheduled time; an additional dose should not be administered to make up for a missed dose.
Risk of MDS and AML. Inform clinician if fatigue/asthenia, fever, weight loss, frequent infections, bruising, unusual bleeding (including hematuria or bloody stool), shortness of breath, abnormal CBC count, or requirement for blood product transfusion occurs.
Risk of bone marrow suppression. Stress importance of hematologic monitoring during talazoparib therapy.
Risk of fetal harm and pregnancy loss. Advise women of reproductive potential to use effective contraception during talazoparib therapy and for ≥7 months after the last dose of the drug. Advise men who are partners of such women, including those who are pregnant, that they should use effective contraception during talazoparib therapy and for ≥4 months after the last dose of the drug. Stress importance of women informing clinicians immediately if they are pregnant or become pregnant during therapy. If pregnancy occurs, advise pregnant women of potential risk to the fetus.
Advise women to avoid breast-feeding while receiving talazoparib and for ≥1 month following discontinuance of therapy.
Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of talazoparib is restricted.

Clinicians may contact the manufacturer (Pfizer) by telephone at 877-744-5675 or consult the Pfizer Oncology together website for specific availability information at: [Web]

Talazoparib Tosylate
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	0.1 mg (of talazoparib)	Talzenna
	Capsules	0.25 mg (of talazoparib)	Talzenna	Pfizer
	Capsules	0.35 mg (of talazoparib)	Talzenna
	Capsules	0.5 mg (of talazoparib)	Talzenna
	Capsules	0.75 mg (of talazoparib)	Talzenna
	Capsules	1 mg (of talazoparib)	Talzenna