Mechanism of Action

Role of PARP enzymes in DNA repair

PARP enzymes and BRCA1/2 proteins both function in DNA repair2,3​​​​​​​

Normal cells

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In normal cells

  • The role of PARP enzymes is to repair single-strand breaks (SSBs) in DNA generated during DNA replication or by DNA damage2

  • The role of BRCA1/2 proteins is to repair double-strand breaks (DSBs) in DNA via a repair mechanism called homologous recombination (HR)3

Cancer cells

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In cancer cells

  • In gBRCA-mutated cells, HR, the mechanism that repairs harmful DSBs in DNA, is defective​​​​​​​3,4

  • These cells become reliant on PARP enzymes, in addition to other, less accurate repair mechanisms, to maintain DNA repair and cell proliferation3,4

  • Cancer cell overreliance on these alternative repair mechanisms can lead to the accumulation of genetic mutations, promoting the formation and survival of tumor cells4​​​​​​​

Dual mechanism of action

TALZENNA is a targeted treatment that induces cancer cell death via 2 complementary mechanisms1*​​​​​​​

PARP enzyme inhibition

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Highly potent PARP trapping

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  • PARP enzymatic inhibition disrupts the subsequent recruitment of DNA repair proteins to the site of SSBs. This results in the accumulation of SSBs, which eventually leads to DSBs during DNA replication5,6
  • In vitro studies demonstrated that BRCA1/2-mutated, HR-deficient cells are highly sensitive to cell death induced by TALZENNA6,7
  • Preclinical studies have shown that TALZENNA has the capacity to trap PARP enzymes to DNA, forming PARP-DNA complexes6,7​​​​​​​
  • In preclinical studies, TALZENNA demonstrated highly potent PARP trapping, which may be correlated with tumor cell death6,7

*TALZENNA can also affect healthy cells.

GIVE YOUR PATIENTS A BIOMARKER-DRIVEN TREATMENT THAT'S ​​​​​​​JUST FOR THEM

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About

  • Mechanism of Action
  • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
  • Identifying Patients With gBRCA Mutations

Safety and tolerability profile

The safety of TALZENNA was evaluated in an open-label, 2:1 randomized Phase 3 study1,8

Review safety profile

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Access and patient support

Personalized patient support and financial assistance resources from Pfizer Oncology Together

Learn more

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Identifying patients with gBRCA ​​​​​​​mutations

Learn about the guidelines for gBRCA ​​​​​​​testing

View testing guidelines

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References:
  1. TALZENNA [prescribing information]. New York, NY: Pfizer Inc.; 2020.
  2. Sonnenblick A, de Azambuja E, Azim HA Jr, Piccart M. An update on PARP inhibitors—moving to the adjuvant setting. Nat Rev Clin Oncol. 2015;12(1):27-41.
  3. Lee J-m, Ledermann JA, Kohn EC. PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol. 2014;25(1):32-40.
  4. Lupo B, Trusolino L. Inhibition of poly(ADP-ribosyl)ation in cancer: old and new paradigms revisited. Biochim Biophys Acta. 2014;1846(1):201-215.
  5. Livraghi L, Garber JE. PARP inhibitors in the management of breast cancer: current data and future prospects. BMC Med. 2015;13:188. doi:10.1186/s12916-015-0425-1.
  6. Gavande NS, VanderVere-Carozza PS, Hinshaw HD, et al. DNA repair targeted therapy: the past or future of cancer treatment? Pharmacol Ther. 2016;160:65-83.
  7. Murai J, Huang SY, Renaud A, et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther. 2014;13(2):433-443.
  8. 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(8):753-763.

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) have been reported in patients who received TALZENNA. Overall, MDS/AML has been reported in 2 out of 584 (0.3%) solid tumor patients treated with TALZENNA in clinical studies. The duration of TALZENNA treatment in these two patients prior to developing MDS/AML was 4 months and 24 months, respectively. Both patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy.

Myelosuppression consisting of anemia, leukopenia/neutropenia, and/or thrombocytopenia have been reported in patients treated with TALZENNA. Grade ≥3 anemia, neutropenia, and thrombocytopenia were reported, respectively, in 39%, 21%, and 15% of patients receiving TALZENNA. Discontinuation due to anemia, neutropenia, and thrombocytopenia occurred, respectively, in 0.7%, 0.3%, and 0.3% of patients.

Monitor complete blood counts for cytopenia at baseline and monthly thereafter. Do not start TALZENNA until patients have adequately recovered from hematological toxicity caused by previous therapy. If hematological toxicity occurs, dose modifications (dosing interruption with or without dose reduction) are recommended. With respect to MDS/AML, for prolonged hematological toxicities, interrupt TALZENNA and monitor blood counts weekly until recovery. If the levels have not recovered after 4 weeks, refer the patient to a hematologist for further investigations. If MDS/AML is confirmed, discontinue TALZENNA.

TALZENNA can cause fetal harm when administered to pregnant women. Advise women of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose. A pregnancy test is recommended for females of reproductive potential prior to initiating TALZENNA treatment. Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment with TALZENNA and for at least 4 months after receiving the last dose. Based on animal studies, TALZENNA may impair fertility in males of reproductive potential. Advise women not to breastfeed while taking TALZENNA and for at least 1 month after receiving the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥20%) of any grade for TALZENNA vs chemotherapy were fatigue (62% vs 50%), anemia (53% vs 18%), nausea (49% vs 47%), neutropenia (35% vs 43%), headache (33% vs 22%), thrombocytopenia (27% vs 7%), vomiting (25% vs 23%), alopecia (25% vs 28%), diarrhea (22% vs 26%), and decreased appetite (21% vs 22%).

The most frequently reported Grade ≥3 adverse reactions (≥10%) for TALZENNA vs chemotherapy were anemia (39% vs 5%), neutropenia (21% vs 35%), and thrombocytopenia (15% vs 2%).

The most common lab abnormalities (≥25%) for TALZENNA vs chemotherapy were decreases in hemoglobin (90% vs 77%), leukocytes (84% vs 73%), lymphocytes (76% vs 53%), neutrophils (68% vs 70%), platelets (55% vs 29%), and calcium (28% vs 16%) and increases in glucose (54% vs 51%), aspartate aminotransferase (37% vs 48%), alkaline phosphatase (36% vs 34%), and alanine aminotransferase (33% vs 37%).

Coadministration with P-gp inhibitors or BCRP inhibitors may increase TALZENNA exposure. If coadministering with the P-gp inhibitors amiodarone, carvedilol, clarithromycin, itraconazole, or verapamil is unavoidable, reduce the TALZENNA dose to 0.75 mg once daily. When the P-gp inhibitor is discontinued, increase the TALZENNA dose (after 3–5 half-lives of the P-gp inhibitor) to the dose used prior to the initiation of the P-gp inhibitor. When coadministering TALZENNA with other known P-gp inhibitors or BCRP inhibitors, monitor patients for potential increased adverse reactions.

For patients with moderate renal impairment, the recommended dose of TALZENNA is 0.75 mg once daily. For patients with severe renal impairment, the recommended dose of TALZENNA is 0.5 mg once daily. No dose adjustment is required for patients with mild renal impairment. TALZENNA has not been studied in patients requiring hemodialysis.

TALZENNA has not been studied in patients with moderate or severe hepatic impairment. No dose adjustment is required for patients with mild hepatic impairment.

TALZENNA is indicated 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-approved companion diagnostic for TALZENNA ​​​​​.

Please see full Prescribing Information.

Indication

TALZENNA is indicated 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-approved companion diagnostic for TALZENNA.