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October 16, 2018, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211651s000lbl.pdf

On October 16, 2018, the Food and Drug Administration approved talazoparib (TALZENNA, Pfizer Inc.), a poly (ADP-ribose) polymerase (PARP) inhibitor, for patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2‑negative locally advanced or metastatic breast cancer. Patients must be selected for therapy based on an FDA-approved companion diagnostic for talazoparib.

Approval was based on EMBRACA (NCT01945775), an open‑label trial randomizing 431 patients (2:1) with gBRCAm HER2‑negative locally advanced or metastatic breast cancer to receive talazoparib (1 mg) or physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). All patients were required to have a known deleterious or suspected deleterious gBRCA mutation and must have received no more than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic 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.

The primary efficacy outcome was progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as assessed by blinded independent central review. Estimated median PFS was 8.6 and 5.6 months in the talazoparib and chemotherapy arms, respectively (HR 0.54; 95% CI: 0.41, 0.71; p<0.0001).

The prescribing information includes warnings and precautions for myelodysplastic syndrome/acute myeloid leukemia, myelosuppression, and embryo-fetal toxicity. Most common (≥20%) adverse reactions of any grade were fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, decreased appetite.

FDA also approved the BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc.) to identify patients with breast cancer with deleterious or suspected deleterious gBRCAm who are eligible for talazoparib. The effectiveness of the BRACAnalysis CDx test was based on the EMBRACA trial population for whom deleterious or suspected deleterious gBRCAm status was confirmed with either prospective or retrospective testing with BRACAnalysis CDx.

The recommended talazoparib dose is 1 mg taken as a single oral daily dose, with or without food.

View full prescribing information for TALZENNA.

FDA granted this application priority review. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Talazoparib for Locally Advanced or Metastatic Human Epidermal Growth Factor Receptor 2 (HER2)–Negative, Germline BRCA (gBRCA) 1 and 2 Mutated Breast Cancer

Author: Kendall Shultes, PharmD BCOP
Assistant Professor, Department of Pharmacy Practice
Belmont University College of Pharmacy
Nashville, TN

What is the potential role for talazoparib in the treatment of locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative, germline BRCA (gBRCA) 1 and 2 mutated breast cancer?

  • Poly (adenosine diphosphate-ribose) polymerase (PARP) enzymes regulate base excision repair of single-strand DNA breaks, and breast cancer susceptibility genes (BRCA) 1 and BRCA 2 are involved in double-strand DNA repair. Mutations in BRCA 1 and 2 result in the loss of the repair mechanism of double-stranded DNA through homologous recombination. With the inhibition of PARP enzymes in BRCA1 and 2 mutated cancers and loss of homologous recombination, single-strand DNA breaks accumulate, which leads to cell death.1 Talazoparib, a PARP 1 and 2 inhibitor, has been shown to induce cancer cell death in cancer lines with germline BRCA (gBRCA) 1 and 2 mutations. Additionally, talazoparib increases the binding of PARP to DNA, leading to increased DNA damage, decreased cell production, and death.2
  • The U.S. Food and Drug Administration (FDA) approval study for talazoparib was EMBRACA, an open-label randomized international phase 3 study in which patients were randomized in a 2:1 fashion to either talazoparib or physician’s choice of chemotherapy (vinorelbine, eribulin, capecitabine, or gemcitabine). All patients were required to have a deleterious or suspected deleterious gBRCA mutation and to have had no more than three prior lines of cytotoxic chemotherapy that included the use of an anthracycline and/or taxane.3
    • The primary endpoint was progression-free survival (PFS) based on Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1. PFS for talazoparib was 8.6 months, compared to 5.6 months in the standard-therapy group (hazard ratio [HR] 0.54; 95% confidence interval [CI]: 0.41–0.71; p < .001). In clinically relevant subgroups that included BRCA mutation type (BRCA1 vs. BRCA2), hormone-receptor status (triple-negative vs. hormone-receptor positive), and prior number of chemotherapy regimens, the risk of disease progression was lower in the talazoparib group.
    • Secondary endpoints included overall survival and response rate. Median overall survival was 22.3 months in the talazoparib group, compared to 19.5 months for the standard-therapy group (HR 0.76; 95% CI: 0.55–1.06, p = .11), although data were immature at the time of trial publication. The response rate, as determined by RECIST criteria and the investigators, was doubled in the talazoparib group, with 62.6% obtaining complete or partial responses (5.5% and 57.1%, respectively), compared to 27.2% for the standard-therapy group (all partial responses).
    • Hematological adverse events were common, with 67.8% of talazoparib patients experiencing events of any grade, compared to 50% in the standard-therapy group. The most common nonhematological adverse event was fatigue for both the talazoparib and standard-therapy groups (50.3% and 42.9%, respectively, all grades).4
    • Patient-reported outcomes were measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and the QLQ-BR23, a breast cancer–specific companion to QLQ-C30. Talazoparib resulted in a significant improvement in overall mean change from baseline in the global health and quality-of-life scale that is part of the QLQ-C30, and standard therapy resulted in a significant deterioration. For breast cancer–specific symptoms, a significant improvement was noted with talazoparib, compared to a nonsignificant change with standard therapy.4
  • Talazoparib has received a Category 1 recommendation from the current National Comprehensive Cancer Network (NCCN) breast cancer guidelines as a preferred single-agent option in the treatment of HER2-negative breast cancer with a gBRCA 1 or 2 mutation in the recurrent or metastatic setting.5
    • It is strongly suggested that patients with HER2-negative disease who are eligible for single-agent therapy undergo gBRCA 1/2 testing.
    • Olaparib, another oral PARP inhibitor, is also FDA approved for use in this setting. NCCN has also designated olaparib as a preferred single-agent option in the treatment of HER2-negative breast cancer in the recurrent or metastatic setting as a Category 1 recommendation.
  • Olaparib, administered by mouth twice daily, was studied in a similar group of advanced breast cancer patients in the OlympiAD study. However, the EMBRACA study included patients with locally advanced disease.6
    • Olaparib also led to an improvement in PFS over standard therapy, with a hazard ratio for disease progression or death of 0.58 (95% CI, 0.43–0.8, p < .001).
  • No direct comparison between olaparib and talazoparib has been conducted. At this time, differences in dosing, adverse events, and cost should be considered when one is making a treatment decision. Both PARP inhibitors have similarly reported adverse events, including hematological toxicities—neutropenia, anemia, and thrombocytopenia, as well as fatigue and headache.
    • Clinically relevant findings for both agents include the development of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), which has been noted in 0.3% of patients receiving talazoparib and in less than 1.5% of patients receiving olaparib.2,7 Although no incidences of MDS or AML development occurred in the EMBRACA or OlympiAD studies, neither agent should be initiated until resolution of prior hematological toxicities has been achieved.3,6 Complete blood counts should be obtained at baseline and monthly thereafter.2,7

What role can the pharmacist play in the management of patients on talazoparib?

  • Talazoparib is administered as 1 mg by mouth daily, with or without food. Capsules should be swallowed whole and not opened or dissolved.2
    • If a dose is vomited, the dose should not be made up. Dosing should resume at the next scheduled administration time.
  • For patients with an estimated creatinine clearance (CrCl) of 30–59 mL/min, dose reduction to 0.75 mg daily is necessary. Talazoparib has not been studied in patients with moderate to severe hepatic impairment or severe renal impairment (when CrCl < 30 mL/min or hemodialysis is required).2
  • The use of talazoparib requires a dose reduction to 0.75 mg once daily when it is given concurrently with P-glycoprotein (P-gp) inhibitors such as amiodarone, carvedilol, clarithromycin, and verapamil. No recommendations are available for dose adjustments in the case of talazoparib-food interactions.2
  • Adverse events (>20%) seen in clinical trials included fatigue (62%), anemia (53%), nausea (49%), neutropenia (35%), headache (33%), thrombocytopenia (27%), alopecia (25%), vomiting (25%), diarrhea (22%), and decreased appetite (21%). The most prevalent grade 3 or 4 adverse events included anemia (39%), neutropenia (21%), and thrombocytopenia (15%).2
  • Therapy with talazoparib should be withheld for hemoglobin <8 g/dL, platelets <50,000/μL, absolute neutrophil count <1,000/μL, or a grade 3 or 4 nonhematological toxicity.2
    • Treatment may be resumed at a reduced dose when hemoglobin is 9 g/dL or higher, platelets are 75,000/μL or higher, and neutrophils are 1,500/μL or higher.
    • For nonhematological toxicity that has resolved to grade 1 or lower, talazoparib may be resumed at a reduced dose or discontinued.
    • On the basis of presentation and occurrence of adverse events, dose reductions are as follows:
      • First dose reduction is to 0.75 mg (three 0.25 mg capsules) daily.
      • Second dose reduction is to 0.5 mg (two 0.25 mg capsules) daily.
      • Third dose reduction is to 0.25 mg (one 0.25 mg capsule) daily.

Clinical Pearls

  • Talazoparib is available in 0.25-mg (ivory cap, white body) and 1-mg capsules (red cap, white body) and should be stored between 68 ̊ F and 77 ̊ F.2
  • The use of talazoparib requires confirmation of gBRCA mutation with the companion diagnostic, BRACAnalysis CDx test.2
  • The use of talazoparib has been studied in the treatment of HER2-negative locally advanced or metastatic breast cancer.3
  • EMBRACA allowed for the prior use of platinum agents before enrollment, provided that the patient had had a disease-free period for at least 6 months. The study did not offer platinum use as a standard therapy for comparison to talazoparib, leaving the comparison between PARP inhibitors and platinum agents still unknown.3
  • Pfizer Oncology Together provides financial assistance for patients with commercial insurance, but the program can also help patients who have other government-issued insurance plans or no insurance find qualifying programs for financial assistance.8,9

References

  1. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917-921.
  2. Talzenna (talazoparib) [package insert]. New York, NY: Pfizer; 2018.
  3. 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.
  4. 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 [supplemental material].
  5. National Comprehensive Cancer Network. Breast Cancer. Version 1.2019. Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed March 18, 2019.
  6. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377:523-533.
  7. Lynparza (olaparib) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals, LP; 2017.
  8. Pfizer Inc. 2018. Financial Assistance Resources for TALZENNA. Available at https://www.talzenna.com/financial-assistance/. Accessed February 6, 2019.
  9. Pfizer Inc. 2018. Pfizer Oncology Together. Available at https://www.pfizeroncologytogether.com. Accessed February 6, 2019.
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