Talazoparib, a potent and selective inhibitor of polyadenosine diphosphate [ADP]-ribose polymerase (PARP), is an antineoplastic agent.1
Talazoparib tosylate is used as a single agent for the treatment of confirmed or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated, human epidermal growth factor receptor type 2 (HER2)-negative locally advanced or metastatic breast cancer.1, 2 An FDA-approved companion diagnostic test (BRACAnalysis CDx®) is required to confirm the presence of mutations in the BRCA genes (BRCA1 and/or BRCA2) prior to initiation of talazoparib therapy.1 Currently available evidence indicates that talazoparib therapy is associated with substantially prolonged progression-free survival and improved response rates compared with standard single-agent chemotherapy in adults with confirmed or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer.1, 2
This indication for talazoparib is based principally on the results of a randomized, open-label, phase 3 study (EMBRACA) in adults with confirmed or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer, with supporting data from an open-label, 2-cohort, phase 2 study (ABRAZO).1, 2, 10, 11, 12
In the EMBRACA study, 431 patients were randomized (stratified by number of prior therapies, hormone receptor status, presence of brain metastases) in a 2:1 ratio to receive either talazoparib (1 mg orally once daily continuously) or investigator's choice of single-agent chemotherapy (capecitabine 1.25 g/m2 orally twice daily for 14 days of each 21-day cycle; eribulin mesylate 1.4 mg/m2 IV on days 1 and 8 of each 21-day cycle; gemcitabine 1.25 g/m2 IV on days 1 and 8 of each 21-day cycle; or vinorelbine 30 mg/m2 IV on days 1 and 8 of each 21-day cycle).1, 2, 4 Treatment was continued until disease progression or unacceptable toxicity occurred or the patient withdrew from the study.1, 2 All patients enrolled in the study were required to have received prior therapy with an anthracycline and/or a taxane in the neoadjuvant, adjuvant, locally advanced, or metastatic setting unless such therapy was contraindicated; however, patients with previously untreated locally advanced or metastatic breast cancer without a history of adjuvant chemotherapy could be enrolled if the patient was a candidate for the control arm.1, 4 Patients whose disease progressed during platinum-based chemotherapy for advanced breast cancer and those who had received prior therapy with a polyadenosine diphosphate [ADP]-ribose polymerase (PARP) inhibitor were excluded from the study.1
In the EMBRACA study, the median age of patients receiving talazoparib was 45 years; 67% were Caucasian, 11% were of Asian ancestry, 4% were black or African American, and 1% were male.1 The median age of patients receiving standard single-agent chemotherapy was 50 years; 75% were Caucasian, 11% were of Asian ancestry, 1% were black or African American, and 2% were male.1 Most of the patients enrolled in the study had an ECOG performance status of 0 or 1 (98%), and confirmed or suspected deleterious BRCA1 or BRCA2 mutation was verified by the companion diagnostic test BRACAnalysis CDx® in 82% of patients.1 Approximately one-half (56%) of all patients had estrogen receptor-positive and/or progesterone receptor-positive breast cancer and 44% were hormone receptor-negative.1 Patients enrolled in the study had received a median of one prior chemotherapy regimen for advanced disease; 38% of patients had previously untreated advanced or metastatic disease, 37% had received one prior chemotherapy regimen, 20% had received 2 prior chemotherapy regimens, and 5% had received 3 or more previous lines of chemotherapy.1 Among talazoparib-treated patients, 91, 85, or 16% of patients had previously received taxane-, anthracycline-, or platinum-containing chemotherapy, respectively.1 The primary measure of efficacy was progression-free survival (as evaluated by a blinded independent central review committee according to Response Evaluation Criteria in Solid Tumors [RECIST]).1, 2
In the EMBRACA study at a median follow-up of 11.2 months, median progression-free survival was 8.6 months in patients receiving talazoparib compared with 5.6 months in those receiving standard single-agent chemotherapy.1, 2 The results of the progression-free survival analysis based on investigator assessment were consistent with the independent blinded central radiologic assessment.1, 2 In addition, patients receiving talazoparib had higher objective response rates (50.2 versus 18.4%) compared with those receiving standard single-agent chemotherapy.1 The median duration of response in patients receiving talazoparib or standard single-agent chemotherapy was 6.4 or 3.9 months, respectively.1 Median overall survival had not been reached at the time of the analysis.1 Results of a subgroup analysis (based on number of prior therapies, hormone receptor status, history of brain metastases) suggested that the drug's effect on progression-free survival was consistent across subgroups.1, 2, 11 Talazoparib substantially improved quality of life (using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30] and BR23) and delayed clinically meaningful deterioration in physical and psychologic functioning and symptoms related to breast cancer and associated treatment.9 At the time of final analysis of the EMBRACA trial, the median duration of follow-up was 44.9 months in the talazoparib group and 36.8 months in the chemotherapy group; median overall survival was 19.3 and 19.5 months in each group, respectively.12
In the ABRAZO study, 84 patients were enrolled into 1 of 2 cohorts based on prior therapy; 49 patients with platinum-sensitive disease (defined as those who achieved a complete or partial response to platinum-containing chemotherapy for at least 8 weeks following the last dose of platinum therapy) were assigned to the platinum-sensitive cohort and 35 patients with heavily pretreated disease (defined as those who had received 3 or more chemotherapy regimens that did not contain a platinum agent) were assigned to the heavily pretreated cohort.10 Patients received talazoparib 1 mg orally once daily until disease progression or unacceptable toxicity occurred.10 The primary measure of efficacy was objective response rate as assessed by an independent central review committee according to RECIST.10 The median age of patients enrolled in the study was 50 years, and patients had received a median of 3 prior therapies for their disease.10 The majority (59%) of patients in the platinum-sensitive cohort had triple-negative breast cancer (estrogen receptor-negative, progesterone receptor-negative, and HER2-negative) compared with 17% of those in the heavily pretreated cohort.10 One-half of all patients had BRCA2 mutation-positive disease and 49% had BRCA1 mutation-positive disease.10 The objective response rate in patients with platinum-sensitive or heavily pretreated disease was 21 or 37%, respectively, with a median duration of response of 5.8 or 3.8 months, respectively; complete response was achieved in 4% of patients with platinum-sensitive disease and in none of those with heavily pretreated disease.10
Updated guidelines from the American Society of Clinical Oncology (ASCO) provide recommendations for treatment of postmenopausal women and men with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer.4000 According to ASCO, combination therapy with a nonsteroidal aromatase inhibitor (e.g., letrozole, anastrozole) and a cyclin-dependent kinase (CDK) 4/6 inhibitor should be offered first line to postmenopausal patients with HR-positive metastatic breast cancer.4000 Although most postmenopausal patients appear to benefit from combination therapy, endocrine monotherapy with an aromatase inhibitor may be the best choice for first-line therapy in some patients; the choice between monotherapy and combination therapy should be based on factors such as disease burden, disease-free interval, patient age, patient choice, and treatment tolerance.4000
Patients with progressive disease during treatment with aromatase inhibitors and patients who develop recurrence within 1 year of adjuvant aromatase inhibitor therapy should be offered fulvestrant and a CDK4/6 inhibitor.4000 Treatment with exemestane and everolimus may be offered, either before or after treatment with fulvestrant, to postmenopausal patients with hormone receptor-positive metastatic disease that progressed during treatment with a nonsteroidal aromatase inhibitor; this combination should not be offered as first-line therapy for patients who relapse more than 12 months from prior nonsteroidal aromatase inhibitor therapy or for those who are naïve to hormonal therapy.4000 Patients with metastatic, hormone receptor-positive, HER2-negative breast cancer with germline BRCA mutations who are no longer benefiting from endocrine therapy may be offered an oral PARP inhibitor as monotherapy in the first-through third-line setting rather than chemotherapy.4000 Consult the ASCO guideline for additional information.4000
In a separate guideline on treatment of patients with HER2-negative metastatic breast cancer that is either endocrine pretreated or hormone receptor-negative, ASCO recommends first-line treatment with chemotherapy, with or without an immune checkpoint inhibitor depending on programmed cell death ligand-1 (PD-L1) status, for patients with metastatic triple-negative breast cancer.4030 In triple-negative breast cancer patients with germline BRCA mutations and progressive disease following chemotherapy in the neoadjuvant, adjuvant, or metastatic disease setting, treatment with olaparib or talazoparib rather than chemotherapy is recommended.4030
Talazoparib is used in combination with enzalutamide for the treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).1 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).1 An FDA-approved test for the detection of HRR gene mutation for use with talazoparib is not currently available.1
This indication for talazoparib is based principally on results from the randomized, double-blind, placebo-controlled, multicenter, phase 3, TALAPRO-2 trial.1, 13 TALAPRO-2 evaluated talazoparib in combination with enzalutamide versus placebo plus enzalutamide as initial therapy in 805 adult men with asymptomatic or mildly symptomatic mCRPC .13 A cohort within the study of 399 patients with HRR gene-mutated mCRPC randomly received talazoparib 0.5 mg daily plus enzalutamide 160 mg daily or enzalutamide 160 mg daily plus placebo until unacceptable toxicity or disease progression.1 All patients received a gonadotropin-release hormone (GnRH) analog or had undergone a prior bilateral orchiectomy and progressed on prior androgen deprivation therapy.1
The median age of the enrolled men was 70 years (range, 41 to 90), 68% were white, 21% Asian, 12% Hispanic/Latino, and 2.8% Black.1 Bone only disease was present in 39% of patients with 15% experiencing visceral disease.1 The most commonly mutated HRR genes (>5%) including co-occurring mutations were BRCA2 (34%), ATM (22%), CDK12 (19%), CHEK2 (18%), and BRCA1 (6%).1
The primary efficacy outcome was radiographic progression-free survival, with overall survival an additional efficacy outcome.1 Results revealed a substantial improvement in the percentage of radiographic progression-free survival events at the pre-specified interim analysis in patients randomized to the combination of talazoparib plus enzalutamide as compared to enzalutamide alone (33% versus 52%).1 The overall survival data were not mature enough at the time of the analysis; however, 24% of patients had expired.1
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.4031 Each of these agents has a randomized clinical trial demonstrating a survival benefit for men with mCRPC.4031 The choice of initial treatment should be driven by adverse effect profile and prior treatment regimens.4031 The 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.4031 Platinum-based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor.4031
Talazoparib tosylate is administered orally once daily.1 The drug may be given without regard to meals.1
The capsules should be swallowed whole and should not be dissolved or opened.1 If the patient vomits or misses a dose, an additional dose should not be taken; take the next prescribed dose at the usual time.1
Store talazoparib at 20-25°C (excursions permitted between 15-30°C).1
Dosage of talazoparib tosylate is expressed in terms of talazoparib.1
The recommended adult dosage of talazoparib as monotherapy for the treatment of confirmed or suspected deleterious germline BRCA-mutated locally advanced or metastatic breast cancer is 1 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1
The recommended adult dosage of talazoparib in combination with enzalutamide for the treatment of HRR gene-mutated metastatic castration-resistant prostate cancer is 0.5 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity.1
Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or have undergone a bilateral orchiectomy.1 Refer to the enzalutamide prescribing information for recommended enzalutamide dosage regimens.1
If adverse reactions occur, consider interruption of therapy or dosage reduction of talazoparib based on severity and clinical presentation.1
Breast Cancer: If dosage reduction from 1 mg once daily is necessary, the recommended dosage is 0.75 mg once daily.1 If dosage reduction from 0.75 mg once daily is necessary, the recommended dosage is 0.5 mg once daily.1 If further dosage reduction is necessary, the dosage should be reduced to 0.25 mg once daily.1 If the toxicity recurs on a dosage of 0.25 mg once daily, discontinue talazoparib therapy.1
Prostate Cancer: If dosage reduction from 0.5 mg once daily is necessary, the recommended dosage is 0.35 mg once daily.1 If dosage reduction from 0.35 mg once daily is necessary, the recommended dosage is 0.25 mg once daily.1 If further dosage reduction is necessary, the dosage should be reduced to 0.1 mg once daily.1 If the toxicity recurs on a dosage of 0.1 mg once daily, discontinue talazoparib therapy.1
For hemoglobin concentrations <8 g/dL, withhold talazoparib therapy.1 When hemoglobin concentrations reach or exceed 9 g/dL, resume talazoparib at a reduced dosage.1
For platelet counts <50,000/mm3, withhold talazoparib therapy.1 When platelet count reaches or exceeds 75,000/mm3, resume talazoparib at a reduced dosage.1
For absolute neutrophil count (ANC) <1000/mm3, withhold talazoparib therapy.1 When ANC reaches or exceeds 1500/mm3, resume talazoparib at a reduced dosage.1
If MDS/AML is confirmed, discontinue talazoparib therapy.1
If grade 3 or 4 nonhematologic toxicity occurs, withhold talazoparib therapy.1 When the nonhematologic toxicity resolves to grade 1 or less, consider dosage reduction of talazoparib or discontinuance of therapy.1
Concomitant Use of Drugs Affecting the P-glycoprotein Transport System
Breast Cancer: Avoid concomitant use of talazoparib with potent inhibitors of P-glycoprotein (P-gp) (i.e., amiodarone, carvedilol, clarithromycin, itraconazole, verapamil);1 if concomitant use of these P-gp inhibitors cannot be avoided, reduce the dosage of talazoparib from 1 mg once daily to 0.75 mg once daily.1 If concomitant use of the P-gp inhibitor is discontinued, return the talazoparib dosage to the dosage used prior to initiation of the P-gp inhibitor (after 3-5 terminal half-lives of the P-gp inhibitor).1
Monitor for increased toxicity and modify the talazoparib dosage regimen as recommended for adverse reactions when talazoparib is coadministered with other P-gp inhibitors.1
No dosage adjustment is required in patients with mild, moderate, or severe hepatic impairment.1
Breast Cancer: For patients with moderate renal impairment (creatinine clearance 30-59 mL/minute), the manufacturer recommends a talazoparib dosage of 0.75 mg once daily.1 For patients with severe renal impairment (creatinine clearance 15-29 mL/minute), the manufacturer recommends a talazoparib dosage of 0.5 mg once daily.1 No dosage adjustment is necessary in patients with mild renal impairment (creatinine clearance 60-89 mL/minute).1
Prostate Cancer: For patients with moderate renal impairment (creatinine clearance 30-59 mL/minute), the manufacturer recommends a talazoparib dosage of 0.35 mg once daily.1 For patients with severe renal impairment (creatinine clearance 15-29 mL/minute), the manufacturer recommends a talazoparib dosage of 0.25 mg once daily.1 No dosage adjustment is necessary in patients with mild renal impairment (creatinine clearance 60-89 mL/minute).1
Talazoparib has not been studied in patients receiving dialysis, and the manufacturer provides no specific dosage recommendations for such patients.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
None.1
Myelodysplastic Syndrome/Acute Myeloid Leukemia
In clinical studies evaluating talazoparib as a single agent in patients with solid tumors, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) were reported in 3 of 788 patients (0.4%).1 In the TALAPRO-2 study, MDS/AML occurred in 2 of 511 patients (0.4%) treated with the combination of talazoparib and enzalutamide and 0 of 517 patients (0%) treated with placebo and enzalutamide.1 The majority of these patients received previous chemotherapy with platinum-containing agents and/or other DNA-damaging antineoplastic agents.1
Monitor complete blood cell (CBC) counts at baseline and then monthly in patients receiving talazoparib.1 In addition, do not initiate talazoparib therapy until patients have adequately recovered from hematologic toxicity caused by previous chemotherapy.1 If prolonged hematologic toxicity occurs during therapy, withhold talazoparib and monitor CBC counts weekly until recovery occurs.1 If hematologic toxicity persists for more than 4 weeks following interruption of therapy, refer patients to a hematologist for further evaluation, including bone marrow analysis and cytogenetic testing of a blood sample.1 If MDS/AML is confirmed, discontinue talazoparib.1
Adverse hematologic effects (e.g., anemia, neutropenia, thrombocytopenia) are frequently reported in patients receiving talazoparib therapy.1 In clinical trials, grade 3 or greater anemia, neutropenia, and thrombocytopenia occurred in 39, 21, and 15%, respectively, of patients receiving talazoparib as a single agent.1 Therapy was discontinued because of anemia, neutropenia, or thrombocytopenia in 0.7, 0.3, or 0.3%, respectively, of patients receiving the drug.1, 4
In the TALAPRO-2 study, grade 3 or greater anemia, neutropenia, and thrombocytopenia occurred in 45, 18, and 8%, respectively, of patients receiving talazoparib in combination with enzalutamide.1 Therapy was discontinued because of anemia, neutropenia, or thrombocytopenia in 7, 3, and 0.4% of patients in the TALAPRO-2 study.1 Overall, 39% of patients in the study required a red blood cell transfusion; 22% required multiple transfusions.1
Do not initiate talazoparib therapy until patients have adequately recovered from hematologic toxicity caused by previous chemotherapy.1 Monitor CBC counts at baseline and then monthly in patients receiving talazoparib.1 Temporary interruption, dosage reduction, or discontinuance of talazoparib may be necessary if hematologic toxicity occurs during therapy with the drug.1 If hematologic toxicity develops and persists for more than 4 weeks following interruption of talazoparib therapy, refer patients to a hematologist for further evaluation, including bone marrow analysis and cytogenetic testing of a blood sample.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action and animal findings, talazoparib may cause fetal harm.1 Embryotoxicity (i.e., embryofetal death, decreased fetal weight) and teratogenicity were observed in pregnant rats receiving talazoparib at exposure levels equivalent to 0.24 times the human exposure at the recommended talazoparib dosage.1 The manufacturer recommends confirmation of pregnancy status prior to initiation of talazoparib; advise females of reproductive potential to use effective contraceptive methods during talazoparib therapy and for at least 7 months after discontinuance of the drug.1 In addition, advise males who are partners of such females, including males partners of pregnant females, to use effective methods of contraception while receiving the drug and for at least 4 months after the drug is discontinued.1 Apprise patients of the potential fetal hazard if talazoparib is used during pregnancy.1
Talazoparib may cause fetal harm if administered to pregnant patients based on its mechanism of action and animal findings.1
Confirm pregnancy status prior to initiation of talazoparib therapy.1
It is not known whether talazoparib is distributed into milk.1 Because of the potential for serious adverse reactions to talazoparib in nursing infants, advise patients to discontinue nursing during talazoparib therapy and for at least 1 month after discontinuance of therapy.1 The effects of the drug on nursing infants or on milk production are unknown.1
Females and Males of Reproductive Potential
Results of animal studies suggest that talazoparib may impair male fertility.1 The effect of the drug on fertility in humans is not known.1
Confirm pregnancy status prior to initiation of talazoparib therapy.1 Advise females of reproductive potential to use effective contraceptive methods during talazoparib therapy and for at least 7 months after discontinuance of the drug.1 In addition, 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 at least 4 months after the drug is discontinued.1
Safety and efficacy of talazoparib have not been established in pediatric patients.1
The pharmacokinetic profile of talazoparib has not been established in patients younger than 18 years of age.1
In clinical studies evaluating talazoparib in patients with advanced solid tumors, 17% of patients were 65 years of age or older and 4% were 75 years of age or older.1 No overall differences in safety were observed between geriatric patients and younger adults.1 However, the possibility of increased sensitivity to the drug in some geriatric patients cannot be ruled out.1
Pharmacokinetics of talazoparib were unaffected following administration of the drug in individuals with mild to severe hepatic impairment.1
In patients with mild (creatinine clearance 60-89 mL/minute), moderate (creatinine clearance 30-59 mL/minute), and severe (creatinine clearance 15-29 mL/minute) renal impairment, systemic exposure to talazoparib is increased by 12, 43, and 163%, respectively, and peak plasma concentrations are increased by 11, 32, and 89%, respectively, compared with individuals with normal renal function.1 Reduce the dosage of talazoparib in patients with moderate or severe renal impairment.1
The pharmacokinetics of talazoparib have not been established in patients receiving dialysis.1
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.1
In vitro studies indicate that talazoparib is not an inhibitor of cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 or an inducer of CYP isoenzymes 1A2, 2B6, or 3A4.1
In vitro, talazoparib is not an inhibitor of uridine diphosphate-glucuronosyltransferases (UGT) 1A1, 1A4, 1A6, 1A9, 2B7, and 2B15.1
In vitro studies indicate that talazoparib is a substrate, but not an inhibitor, of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1 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.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Talazoparib undergoes minimal hepatic metabolism; drug interactions are unlikely with inhibitors or inducers of CYP isoenzymes.1, 4
Drugs Affecting Efflux Transport Systems
Concomitant use of talazoparib with inhibitors of P-gp may result in increased systemic exposure of talazoparib.1 In a population pharmacokinetic analysis, concomitant administration of a potent P-gp inhibitor (i.e., amiodarone, carvedilol, clarithromycin, verapamil) with talazoparib increased the systemic exposure of talazoparib by approximately 45% and resulted in an increase in talazoparib dosage reductions.1, 4 Administration of talazoparib with itraconazole (a potent P-gp inhibitor) in patients with advanced solid tumors increased systemic exposure of talazoparib by 56%.1 However, concomitant use of talazoparib with a moderate or weak P-gp inhibitor (i.e., azithromycin, atorvastatin, diltiazem, felodipine, fluvoxamine, quercetin) in clinical studies did not have a clinically meaningful effect on systemic exposure to talazoparib.1, 4
Breast Cancer: Avoid concomitant use of talazoparib with potent P-gp inhibitors such as amiodarone, carvedilol, clarithromycin, itraconazole, or verapamil;1 if concomitant use of these P-gp inhibitors cannot be avoided, reduce the dosage of talazoparib from 1 mg once daily to 0.75 mg once daily.1 If concomitant use of the P-gp inhibitor is discontinued, return the talazoparib dosage to the dosage used prior to initiation of the P-gp inhibitor (after 3-5 terminal half-lives of the P-gp inhibitor).1 Monitor patients receiving talazoparib concomitantly with a moderate or weak P-gp inhibitor for signs of talazoparib toxicity.1, 4 If adverse effects occur, temporary interruption of talazoparib therapy followed by dosage reduction may be necessary.4
Prostate Cancer: The effect of concurrent use of P-gp inhibitors on talazoparib exposure when talazoparib is taken in combination with enzalutamide has not been evalutated.1 Monitor patients for increased adverse reactions and potentially modify the talazoparib dosage regimen.1
In patients with advanced solid tumors, coadministration of talazoparib with rifampin increased peak serum levels of talazoparib by 37% with no effect on systemic exposure to talazoparib.1
Although not specifically studied in drug interaction studies to date, concomitant use of talazoparib with inhibitors of BCRP may result in increased systemic exposure of talazoparib.1
If concomitant use cannot be avoided, monitor patients for signs of talazoparib toxicity and modify the talazoparib dosage regimen.1
Drugs Affecting Gastric Acidity
Concomitant administration of talazoparib with drugs that reduce gastric acidity such as proton-pump inhibitors, antacids, and histamine H2-receptor antagonists does not have a clinically meaningful effect on absorption of talazoparib.1, 4
Talazoparib, a potent and selective inhibitor of mammalian poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzymes, including PARP-1 and PARP-2, is an antineoplastic agent.1, 5, 6 PARP enzymes are involved in normal cellular homeostasis, including DNA transcription, cell cycle regulation, and DNA repair.4, 5 In vitro studies have demonstrated that talazoparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, which result in DNA damage, decreased cell proliferation, and apoptosis.1, 4 PARP inhibitors, such as talazoparib, appear to be selective for tumor cells that harbor certain homologous recombination deficiencies, including those harboring BRCA1 and BRCA2 mutations.7 In vitro, talazoparib is at least 18- or 37-fold more potent than rucaparib and olaparib in BRCA-deficient or phosphatase and tensin homolog (PTEN)-deficient tumor cells lines, respectively.5, 7 In vitro, talazoparib is 922- and 231-fold more potent than rucaparib and olaparib in estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor type 2 (HER2)-negative breast tumor cell lines harboring BRCA1 mutation.7 In addition, talazoparib demonstrated antitumor activity in patient-derived xenograft tumor models harboring either mutated or wild-type BRCA1/2.1
Talazoparib exhibits linear pharmacokinetics over the dosage range of 0.025-2 mg.1 Following oral administration, the median time to peak plasma concentrations of talazoparib is 1-2 hours.1 Following repeated oral administration of talazoparib at a dosage of 1 mg daily, the median accumulation ratio of talazoparib is 2.3-5.2.1 Steady-state concentrations are reached within 2-3 weeks.1 Administration of talazoparib (single 0.5-mg dose) with a high-fat, high-calorie meal (800-1000 calories with fat accounting for approximately 50-75% of the caloric content) decreased the rate of absorption (time to peak concentrations delayed by 1-4 hours) and the mean peak plasma concentrations (decreased by 46%), but did not substantially affect the extent of absorption.1 Talazoparib undergoes minimal hepatic metabolism.1 Talazoparib is metabolized by mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluorotalazoparib, and glucuronide conjugation.1 Following oral administration of a radiolabeled dose of talazoparib, approximately 68.7% of the radioactivity was recovered in urine (54.6% of the dose as unchanged drug) and 19.7% was recovered in feces (13.6% of the dose as unchanged drug).1 In vitro, talazoparib is 74% bound to plasma proteins, and binding is independent of talazoparib concentration.1 The mean terminal half-life of the drug is 90 hours.1
The pharmacokinetics of talazoparib do not appear to be affected substantially by age (18-88 years), sex, race, or body weight (36-162 kg).1
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. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
Talazoparib tosylate can only be obtained through designated specialty pharmacies.3 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]
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 0.1 mg (of talazoparib) | ||
Capsules | 0.25 mg (of talazoparib) | Talzenna® | Pfizer | |
Capsules | 0.35 mg (of talazoparib) | Talzenna® | ||
Capsules | 0.5 mg (of talazoparib) | Talzenna® | Pfizer | |
Capsules | 0.75 mg (of talazoparib) | Talzenna® | ||
Capsules | 1 mg (of talazoparib) | Talzenna® |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions October 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Pfizer. Talzenna® (talazoparib tosylate) capsules prescribing information. New York, NY; 2024 Feb.
2. Litton JK, Rugo HS, Ettl J et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med . 2018; 379:753-763. [PubMed 30110579]
3. Pfizer. Specialty pharmacy distribution network. From the Pfizer Oncology together® website. 2019 Jan. Accessed 2024 Aug 27. [Web]
4. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 211651Orig1s000: Multi-discipline review. From FDA website. [Web]
5. Nur Husna SM, Tan HT, Mohamud R et al. Inhibitors targeting CDK4/6, PARP and PI3K in breast cancer: a review. Ther Adv Med Oncol . 2018; 10:1758835918808509. [PubMed 30542378]
6. Guney Eskiler G, Cecener G, Egeli U et al. BMN 673 (talazoparib): A potent PARP inhibitor for triple negative breast cancer with different genetic profile. J Biochem Mol Toxicol . 2019; :e22286. [PubMed 30672063]
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