On October 16, 2018, the poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib (Talzenna) was approved for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer.1,2
Patients must be selected for therapy based on a U.S. Food and Drug Administration (FDA)-approved companion diagnostic for talazoparib. The FDA also approved the BRACAnalysis CDx test to identify patients with breast cancer with deleterious or suspected deleterious germline BRCA-mutated who are eligible for talazoparib.
Supporting Efficacy Data
Approval was based on findings in the phase III open-label EMBRACA trial (ClinicalTrials.gov identifier NCT01945775), in which 431 patients (2:1) with germline BRCA-mutated HER2‑negative locally advanced or metastatic breast cancer were randomly assigned 2:1 to receive talazoparib at 1 mg daily (n = 287) or physician’s choice of chemotherapy (n = 144; capecitabine, eribulin [Halaven], gemcitabine, or vinorelbine).2,3 Patients were required to have received no more than three prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease and had to have received treatment with an anthracycline or a taxane (unless contraindicated) in the neoadjuvant, adjuvant, or metastatic setting. Randomization was stratified by prior use of chemotherapy for metastatic disease, triple-negative disease status, and history of central nervous system (CNS) metastasis.
Talazoparib has warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia, myelosuppression, and embryofetal toxicity.
In the talazoparib group, 91% had received prior taxane therapy and 85% had received prior anthracycline therapy in any setting, with 16% of the talazoparib group and 21% of patients in the chemotherapy group having received prior platinum treatment in any setting. The median number of prior cytotoxic regimens for patients with advanced breast cancer was 1; 38% had received no prior cytotoxic regimens for advanced or metastatic disease, 37% received 1, 20% received 2, and 5% received 3 or more prior cytotoxic regimens.
The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors, version 1.1, on blinded independent central review. Median progression-free survival was 8.6 months in the talazoparib group vs 5.6 months in the chemotherapy group (hazard ratio [HR] = 0.54, P < .0001). Results were consistent across stratification factors.
Among 219 vs 114 patients with measurable disease, overall response rates were 50.2% vs 18.4%, and median durations of response were 6.4 vs 3.9 months. Overall survival data were not mature at the time of analysis.
How It Works
Talazoparib is an inhibitor of PARP enzymes, including PARP1 and PARP2, which play a role in DNA repair. Studies in cancer cell lines that harbored defects in DNA repair genes, including BRCA1 and BRCA2, have shown that talazoparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage, decreased cell proliferation, and apoptosis. Talazoparib antitumor activity was observed in xenograft breast cancer tumor models expressing mutated or wild-type BRCA1 and BRCA2.
How It Is Used
Patients must be selected for the treatment of advanced breast cancer with talazoparib based on the presence of germline BRCA mutations, as detected by an FDA-approved companion diagnostic.
The recommended dose of talazoparib in the current indication is 1 mg taken orally once daily, with treatment continued until disease progression or unacceptable toxicity. Recommended dose reductions for adverse events are stepwise to 0.75, 0.5, and 0.25 mg daily. Treatment should be discontinued if more than three dose reductions are required.
The recommended starting dose in patients with moderate renal impairment is 0.75 mg once daily. Talazoparib has not been studied in patients with severe renal impairment or patients requiring hemodialysis.
For hematologic adverse events of decreases in hemoglobin to < 8 g/dL, platelets to < 50,000/μL, and neutrophils to < 1,000/ μL, talazoparib should be withheld until levels resolve to ≥ 9 g/ dL, ≥ 75,000/μL, and ≥ 1,500/μL, respectively, with treatment resumed at a reduced dose. For nonhematologic grade 3 or 4 adverse events, treatment should be withheld to grade ≤ 1; resumption at a reduced dose can be considered or treatment discontinued.
Coadministration with P-glycoprotein (P-gp) inhibitors including amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil resulted in an approximate 45% increase in talazoparib exposure. If coadministration with these P-gp inhibitors cannot be avoided, the dose of talazoparib should be reduced. When the P-gp inhibitor is discontinued, the dose of talazoparib used before reduction can be resumed after 3 to 5 half-lives of the inhibitor.
Patients receiving P-gp inhibitors not mentioned above should be monitored for potential increased adverse reactions. Patients receiving concomitant breast cancer resistance protein inhibitors should be monitored for potential increased adverse reactions.
The most common adverse events of any grade in the talazoparib group in the EMBRACA trial were fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, and decreased appetite. The most common grade 3 or 4 adverse events included anemia, neutropenia, and thrombocytopenia.
Dosing interruptions due to adverse events occurred in 66% of patients who received talazoparib vs 60% of patients who received standard therapy, and dose reductions due to any cause occurred in 53% vs 40%. Permanent discontinuation of treatment due to adverse events occurred in 6% in the talazoparib group vs 9% in the standard therapy group.
Talazoparib carries warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), myelosuppression, and embryofetal toxicity. MDS/AML has been observed in 0.3% of patients receiving talazoparib for solid tumors.
Patients should be monitored for hematologic toxicity at baseline and monthly thereafter; treatment should be discontinued if MDS/AML is confirmed. Women should be advised not to breastfeed during talazoparib therapy. ■
1. U.S. Food and Drug Administration: FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm623540.htm. Accessed November 26, 2018.
2. Talzenna (talazoparib) capsules prescribing information, Pfizer Inc, October 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/211651s000lbl.pdf. Accessed November 26, 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 379:753-763, 2018.