Talazoparib Receives FDA Approval for Locally Advanced or Metastatic BRCA Mutation-Positive Breast Cancer

On 16 October 2018, the United States Food and Drug Administration (FDA), for the treatment of germline (hereditary) BRCA mutation (gBRCAm)-positive, HER2-negative, locally advanced or metastatic breast cancer, approved a poly (ADP-ribose) polymerase (PARP) inhibitor, talazoparib (Talzenna) , a targeted therapy pill.

The approval is based on EMBRACA , a phase-3 clinical trial. This study enrolled 431 patients with gBRCAm-positive, locally (regionally) advanced or metastatic breast cancer. Patients were randomly assigned to two groups in a 2:1 ratio; the experimental arm received talazoparib at 1 mg daily, while the control arm received chemotherapy chosen by the oncologist (capecitabine, eribulin, gemcitabine or vinorelbine).

Study inclusion criteria: detection of a hereditary BRCA mutation (deleterious or suspected deleterious gBRCA mutation). Having previously received no more than 3 lines of chemotherapy for locally advanced or metastatic breast cancer. Neoadjuvant, adjuvant and / or having received treatment with an anthracycline and / or a taxane during metastatic disease.

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The primary (main) endpoint that the EMBRACA study aimed to measure was determined as the duration of progression-free survival (keeping the disease under control with treatment / survival without progression).

The most important result of the study was that estimated median progression-free survival was 8.6 in those receiving talazoparib, compared with 5.6 months in the chemotherapy arm. Talazoparib was found to reduce the risk of cancer worsening by % 46 compared with chemotherapy.

With talazoparib treatment, the most common (≥% 20) reactions of any grade are the following side effects, are fatigue, anemia (low red blood cell levels), nausea, neutropenia, headache, thrombocytopenia (risk of bleeding), vomiting, alopecia (hair loss), diarrhea and decreased appetite. Prescribing information includes warnings and precautions for myelodysplastic syndrome / acute myeloid leukemia, myelosuppression (anemia and neutropenia due to bone marrow suppression) and embryo-fetal toxicity.

The FDA also approved the BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc.) to identify breast cancer patients with hereditary BRCA mutations who are eligible for talazoparib.

The recommended talazoparib doseis a capsule taken 1 time daily at 1 mg, with or without food.

Use of PARP Inhibitors in Cancer

Previously, on 19 January 2018, another PARP inhibitor for hereditary BRCA mutation-positive breast cancer, olaparib (Lynparza) had received FDA approval. Unlike olaparib, talazoparib received approval not only for metastatic disease but also for locally (regionally) advanced breast cancer. In addition, olaparib is taken 2 times daily, while talazoparib is taken 1 time daily. Their treatment efficacy is similar ; another difference between these two drugs is that talazoparib appears to suppress the bone marrow somewhat more.

The PARP inhibitors that have received FDA approval to date can be seen below:

1. Talazoparib (brand name Talzenna, company Pfizer): FDA-approved on 30 October 2018 for locally advanced and metastatic gBRCAm breast cancer
2. Niraparib (brand name Zejula, company Tesaro): FDA-approved on 27 March 2017 for the treatment of recurrent ovarian cancer
3. Olaparib (brand name Lynparza, company AstraZeneca): FDA-approved on 19 December 2014 for advanced ovarian cancer; on 17 August 2017, the tablet formulation for ovarian cancer maintenance treatment; on 12 January 2018 for the treatment of gBRCAm metastatic breast cancer
4. Rucaparib (brand name Rubraca, company name Clovis Oncology): accelerated approval on 19 December 2016 for advanced ovarian cancer; FDA-approved on 6 August 2018 for maintenance treatment of recurrent ovarian cancer
5. Veliparib (company AbbVie): not yet FDA-approved

How Do PARP Inhibitors Work?

Because cancer cells divide much more frequently and rapidly than normal cells, more DNA damage, or mutations, occurs. When DNA damage occurs, various intracellular mechanisms become active and either repair the damage or, if the damage is beyond repair, the cell undergoes apoptosis . Both PARP and BRCA play a role in DNA repair . When niraparib, a PARP inhibitor, is used in ovarian cancer, the cancer cell partially loses its ability to repair its DNA. If these cells also have a BRCA mutation, the cancer cells' ability to repair their DNA and remain immortal is reduced much further.