On June 21, 2019 Pfizer Inc. (NYSE:PFE) reported that the European Commission approved TALZENNA (talazoparib), an oral poly (ADP-ribose) polymerase (PARP) inhibitor, as monotherapy for the treatment of adult patients with germline breast cancer susceptibility gene (gBRCA)1/2-mutations, who have human epidermal growth factor receptor 2-negative (HER2-) locally advanced (LA) or metastatic breast cancer (MBC) (Press release, Pfizer, JUN 21, 2019, View Source [SID1234537211]). Patients should have been previously treated with an anthracycline and/or a taxane in the (neo)adjuvant, locally advanced or metastatic setting unless patients were not suitable for these treatments. Patients with hormone receptor-positive (HR+) breast cancer should have been treated with a prior endocrine-based therapy, or be considered unsuitable for endocrine-based therapy.1 This approval follows the medicine’s approval by the U.S. Food and Drug Administration (FDA) in October 2018.
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"Today’s approval of TALZENNA for certain patients with advanced-stage breast cancer and an inherited BRCA mutation is the latest example of our successful precision medicine approach to drug development," said Andreas Penk, M.D., Regional President, Oncology International Developed Markets at Pfizer. "This important milestone builds on Pfizer’s decades-long legacy of developing therapies that improve outcomes for patients with breast cancer. We are thrilled that we can now offer these patients in Europe, who are often diagnosed at a younger age and have limited treatment options, an effective, once-daily, alternative treatment to chemotherapy."
The European Commission’s approval of TALZENNA, which was acquired as part of Pfizer’s acquisition of Medivation, is based on results from the EMBRACA trial – the largest Phase 3 study of a PARP inhibitor in gBRCA-mutated, HER2- LA or MBC. The global trial evaluated once-daily TALZENNA compared to physician’s choice standard chemotherapy (capecitabine, eribulin, gemcitabine or vinorelbine) in patients with an inherited BRCA1/2 mutation in triple-negative or HR+/HER2- LA or MBC who may have received up to three prior cytotoxic chemotherapy regimens for their advanced disease. The primary endpoint was progression-free survival (PFS), as assessed by blinded independent central review (BICR).1,2
"In the EMBRACA trial, TALZENNA reduced the risk of disease progression by 46 percent and more than doubled the overall response rate compared to chemotherapy," said Johannes Ettl, M.D., Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich in Germany and an investigator in the EMBRACA trial. "This improvement in outcomes for patients treated with TALZENNA reinforces the increasingly key role of genetic testing in treatment decision-making for patients with locally advanced or metastatic breast cancer."
In the EMBRACA trial, TALZENNA significantly outperformed chemotherapy, extending median PFS to 8.6 months compared to 5.6 months for those treated with standard chemotherapy [95% CI: 7.2-9.3 vs. 4.2-6.7, respectively]. The superior PFS benefit with TALZENNA was observed across prespecified patient populations, including patients with triple-negative breast cancer, HR+/HER2- disease, with or without a history of CNS metastasis, and those who received prior cytotoxic chemotherapy regimens. Secondary endpoints from the EMBRACA trial included objective response rate (ORR), overall survival (OS) and safety. TALZENNA demonstrated an ORR of 62.6% (95% CI: 55.8-69.0), more than double that in the standard chemotherapy arm (27.2%) (95% CI: 19.3-36.3). OS is an event-driven endpoint and the data are not yet mature.1
Based on pooled data from patients who received 1 mg TALZENNA in clinical studies for solid tumors, the most common adverse reactions (≥ 25%) of patients receiving TALZENNA were fatigue (57.1%), anemia (49.6%), nausea (44.3%), neutropenia (30.2%), thrombocytopenia (29.6%) and headache (26.5%). Grade 3 or higher adverse reactions (≥ 10%) in patients treated with TALZENNA were anemia (35.2%), neutropenia (17.4%) and thrombocytopenia (16.8%).1
About EMBRACA
The pivotal, Phase 3, open-label, 2:1 randomized EMBRACA trial is the largest Phase 3 trial of a PARP inhibitor in gBRCA-mutated, HER2- LA or MBC. The trial evaluated TALZENNA (1 mg once daily) compared to physician’s choice chemotherapy (capecitabine, eribulin, gemcitabine or vinorelbine) in 431 patients with an inherited BRCA1/2 mutation and locally advanced or metastatic triple-negative or HR+/HER2- breast cancer who may have received up to three prior cytotoxic chemotherapy regimens. Of the patients enrolled, 190 were from European countries, such as Belgium, France, Germany, Ireland, Italy, Poland, Spain and the United Kingdom. The primary endpoint was PFS, as assessed by BICR. Safety, ORR and OS were key secondary endpoints.1,2
Primary results from the EMBRACA trial were published in the New England Journal of Medicine, simultaneous to the online publication of patient-reported outcomes data in Annals of Oncology in August 2018.2,3
For more information on the EMBRACA trial, go to www.clinicaltrials.gov.
About Germline (Inherited) BRCA-Mutated Breast Cancer
BRCA1 and BRCA2 are human genes that produce proteins involved in DNA repair. When either of these genes is altered or mutated, DNA repair may not progress correctly. This can lead to the development of certain types of cancer such as breast cancer.4BRCA mutations can be hereditary (germline) or occur spontaneously (somatic).5 Together, germline BRCA1 and BRCA2 mutations account for about 25 to 30% of hereditary breast cancers and approximately 3 to 6% of all breast cancers.5,6,7,8,9
Epidemiologic studies indicate that individuals with gBRCA-mutated breast cancer are diagnosed in their 30s-40s, which is approximately 20 years younger than the overall breast cancer population.10,11
BRCA-mutated breast cancer is metastatic if the disease has spread beyond the breast or to other parts of the body, including the bones, liver, lung or brain.12 There is currently no cure for MBC, the most advanced stage (stage IV) of the disease. The goal of treatment is to delay or slow disease progression while maintaining quality of life.13,14
Current European and U.S. clinical guidelines recommend gBRCA testing to inform therapeutic considerations for HER2- LA or MBC patients.15,16
About talazoparib
Talazoparib is an inhibitor of PARP enzymes, which play a role in DNA repair. Preclinical studies suggest that talazoparib may work by blocking PARP enzyme activity and trapping PARP at the site of DNA damage, leading to decreased cancer cell growth and cancer cell death. Talazoparib anti-tumor activity also was observed in human patient-derived xenograft breast cancer tumor models that expressed mutated or wild-type BRCA1/2.1
In addition to gBRCA-mutated LA or MBC, talazoparib is being evaluated in several ongoing clinical trials in breast and other cancers, including early triple-negative breast cancer and prostate cancer, as well as other novel combinations with targeted therapies and studies with immunotherapy in various solid tumors.
Indication in the U.S.
TALZENNA (talazoparib) is approved in the U.S. for the treatment of adult patients with deleterious or suspected deleterious germline breast cancer susceptibility gene (gBRCA)‑mutated (gBRCAm) human epidermal growth factor receptor 2‑negative (HER2-), locally advanced or metastatic breast cancer. Select patients for therapy based on an FDA-approved companion diagnostic for TALZENNA.17
TALZENNA (talazoparib) Important Safety Information from the U.S. Prescribing Information
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) have been reported in patients who received TALZENNA. Overall, MDS/AML have 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 (≥5%) for TALZENNA vs chemotherapy were anemia (39% vs 5%), neutropenia (21% vs 36%), 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 co-administering 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. No dose adjustment is required for patients with mild renal impairment. TALZENNA has not been studied in patients with severe renal impairment or 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.