FDA Approves Talazoparib for BRCA-Mutated, HER2-Negative Breast Cancer

The FDA has approved talazoparib (Talzenna) for patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer, according to Pfizer, the manufacturer of the PARP inhibitor.

In addition, the FDA approved the BRACAnalysis CDx test, developed by Myriad Genetic Laboratories, Inc., to identify patients with breast cancer with deleterious or suspected deleterious germline BRCA-mutated disease who are eligible for talazoparib. Patients must be selected for talazoparib based on this FDA-approved companion diagnostic.

“We congratulate Pfizer on obtaining FDA approval of Talzenna for certain patients living with metastatic breast cancer, and we are excited to expand the use of BRACAnalysis CDx as the companion diagnostic test,” said Lloyd Sanders, president of Myriad Oncology. “We estimate there are more than 60,000 patients diagnosed with or who progress to metastatic breast cancer in the United States every year who qualify for a BRACAnalysis CDx test.”

The decision is based on findings from the international, open-label phase III EMBRACA trial, in which talazoparib reduced the risk of disease progression or death by 46% versus chemotherapy in patients with BRCA-positive advanced breast cancer. In the study, 431 patients with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer were randomized in a 2:1 ratio to receive 1 mg daily of oral talazoparib (n = 287) or physician’s choice of chemotherapy (n = 144), which included capecitabine (received by 44% of patients), eribulin (40%), gemcitabine (10%), and vinorelbine (7%).

To be eligible for enrollment, patients were required to have received no more than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease. Moreover, patients must have received treatment with an anthracycline and/or a taxane, unless contraindicated, in the neoadjuvant, adjuvant, and/or metastatic setting. The primary endpoint was progression-free survival (PFS), as assessed by blinded independent central review. Secondary endpoints were overall survival (OS), safety, and overall response rate (ORR).

Results demonstrated that, at a median follow-up of 11.2 months, the median PFS was 8.6 months (95% CI, 7.2-9.3) in the talazoparib arm and 5.6 months (95% CI, 4.2-6.7) in the chemotherapy arms, respectively (HR, 0.54; 95% CI: 0.41-0.71; P <.0001). The ORR was 62.6% (95% CI, 55.8-69.0) versus 27.2% (95% CI, 19.3-36.3), respectively (odds ratio, 4.99; 95% CI, 2.9-8.8; 2-sided P value <.0001). The PFS benefit with talazoparib was observed across all predetermined patient subgroups.

Patient characteristics were mostly well balanced between the 2 arms, with a few variations of note. In the talazoparib arm, 63.4% of patients were aged <50 years, compared with 46.5% of patients in the control arm. Fifteen percent of patients receiving the PARP inhibitor had a history of CNS metastasis, compared with 13.9% in the chemotherapy group. In the talazoparib group, 37.6% of patients had a disease-free interval (initial diagnosis to advanced breast cancer) of under 12 months versus 29.2% in the chemotherapy arm.

The median duration of treatment was 6.1 months versus 3.9 months for talazoparib versus chemotherapy, respectively. Among patients with measurable disease, the complete response (CR) rate in the talazoparib arm was 5.5%, the partial response (PR) rate was 57.1%, and the stable disease rate was 21.0%. The corresponding rates in the physician’s choice arm were 0, 27.2%, and 31.6%, respectively.

The median duration of response was 5.4 months (95% CI, 4.2-6.3) with talazoparib and 3.1 months (95% CI, 2.8-5.6) with chemotherapy (HR, 0.43; 95% CI, 0.27-0.70; P = .0005). Moreover, the 1-year probability of sustained response was 23% vs 0%, respectively.

OS data are not yet mature; however, an interim OS analysis found a positive trend favoring talazoparib, with a 24% reduction in the risk of death. The median OS was 22.3 months (95% CI, 18.1-26.2) with the PARP inhibitor versus 19.5 months (95% CI, 16.3-22.4) with chemotherapy (HR, 0.76; 95% CI, 0.54-1.06; P = .105).

The indication for talazoparib includes warnings and precautions for myelodysplastic syndrome/acute myeloid leukemia, myelosuppression, and embryo-fetal toxicity. The most common all-grade adverse events associated with fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, and decreased appetite.

The efficacy of BRACAnalysis CDx was based on the EMBRACA trial patient population for whom deleterious or suspected deleterious germline BRCA-mutated status was confirmed with either prospective or retrospective testing with BRACAnalysis CDx.

BRACAnalysis CDx is defined as an in vitro diagnostic device created for the qualitative detection and classification of variants in the protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes using genomic DNA obtained from whole blood specimens collected in EDTA. Moreover, single nucleotide variants and small insertions and deletions are identified by polymerase chain reaction (PCR) and Sanger sequencing, while large deletions and duplications in BRCA1 and BRCA2 are detected using multiplex PCR.

BRACAnalysis CDx also has a diagnostic indication for the detection of deleterious or suspected deleterious mutations in BRCA1 and BRCA2 genes for patients with ovarian cancer to select therapy for olaparib (Lynparza) and/or rucaparib (Rubraca).

“Myriad’s BRACAnalysis CDx test was shown in the EMBRACA trial to accurately identify certain patients with a germline BRCA-mutation who may benefit from Talzenna,” said Johnathan Lancaster, MD, PhD, chief medical officer of Myriad Genetics. “It is important for patients to know their BRACAnalysis CDx results so they can fully understand their treatment options.”

Litton JK, Rugo HS, Ettl J, et al. A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician’s choice of therapy in patients with advanced breast cancer and a germline BRCA-mutation. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS6-07.