FDA approves PARP inhibitor talazoparib for BCRA-positive, HER2‑negative advanced breast cancer

The US Food and Drug Administration (FDA) approved talazoparib (Talzenna, Pfizer Inc.) for patients with advanced BCRA-positive, HER2‑negative locally advanced or metastatic breast cancer. Talazoparib is administered orally and belongs to the class of drugs called poly (ADP-ribose) polymerase (PARP) inhibitors, which block the enzymes involved in repairing of damaged DNA.

BRCA mutation is responsible for 25-30% of all hereditary breast cancers and 5-10% of all breast cancers. The FDA has also approved the BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc.) to identify patients with breast cancer with deleterious or suspected deleterious germline BRCA mutation who are eligible for talazoparib.

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.

The approval is based on results of international EMBRACA (NCT01945775) trial, an open-labeled, RCT involving 431 patients with gBRCAm HER2‑negative locally advanced or metastatic breast cancer. The other inclusion criteria were having received prior treatment with an anthracycline and/or a taxane (unless contraindicated) in the neoadjuvant, adjuvant, and/or metastatic treatment setting. Patients were excluded if they have received more than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease.

The patients were randomized to receive 1 mg oral talazoparib or physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS), as assessed by a blinded independent central review.

At the median follow-up of 11.2 months, talazoparib reduced the risk of disease progression or death by 46% versus chemotherapy. Patients in talazoparib arm demonstrating median survival of 8.6 months as opposed to 5.6 months in the chemotherapy arm.

Patients on talazoparib also showed higher objective response rate (ORR) as compared to patients on other chemotherapy drugs (62.6% vs. 27.2%; odds ratio, 4.99; 95% CI, 2.9-8.8; 2-sided P value <.0001). The FDA defines ORR as the “proportion of patients with a tumor size reduction of a predefined amount and for a minimum period of time,” and ORR is one of the many oncology endpoints for the approval of cancer drugs and biologics.

Most commonly reported side effects of the drug include nausea, headache, fatigue, anemia, neutropenia, thrombocytopenia, vomiting, alopecia, diarrhea, and decreased appetite. The drug also comes with a warning and precautions for myelodysplastic syndrome/acute myeloid leukemia, myelosuppression, and embryo-fetal toxicity.

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).

FDA approval

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Double Mastectomy reduces the risk of death in BRCA1 mutation carriers but not in BRCA2 carriers

An interesting paper recently presented at the 11th European Breast Cancer Conference in Barcelona, Spain stratifies the risk of death based on the type of BRCA gene mutation. Healthy women who are carriers of breast cancer-causing mutation in the BRCA1 gene and undergo the bilateral mastectomy, not only reduce their risk of developing breast cancer but also their chances of dying.

But, this is not the case with women who are carriers of the BRCA2 gene mutation, in whom the risk of dying was not reduced if women had the bilateral risk-reducing mastectomy (BRRM) or chose to have a close surveillance.

This is the first prospective study of healthy women with BRCA1 gene mutation (1696 women) or BRCA2 mutation (1139 women) who either chose to undergo BRRM or close surveillance, to compare their overall risk of dying from any cause and their risk of dying from breast cancer.

The women were recruited from the National Hereditary Breast and Ovarian Cancer Netherlands (HEBON) database and did not have any previous history of cancer. They also have not undergone breast or ovaries removal at the time of DNA diagnosis of BRCA1 or BRCA2 gene mutation.

The average follow-up in both the mutation types was between 9 to 11 years. In BRCA1 group, women who had undergone BRRM had considerable more chances of overall survival (90%) and breast cancer-specific survival (99.6%) compared to surveillance group where the overall survival was 83% and breast cancer-specific survival was 93%.

In the BRCA2 group, the overall survival and breast cancer specific survival did not differ much among both the groups.

Dr. Annette Heemskerk-­Gerritsen, a post-­doctoral researcher at the Erasmus University Medical Centre Rotterdam, The Netherlands said at the conference, “the difference in the chances of dying from breast cancer between BRCA1 and BRCA2 gene mutation carriers supports the idea that these two mutations result in different types of tumors.”

“We observed that BRCA2-­associated breast cancers were diagnosed with more favorable characteristics than BRCA1-­associated breast cancers. BRCA2-­associated cancers were diagnosed at an older age, better differentiated, and were more likely to have receptors for the hormones estrogen and progesterone and for the human epidermal growth factor (HER2), suggesting that BRCA2  mutation carriers face a better prognosis at diagnosis than BRCA1 mutation carriers,” She further added.

The results of the study mean that women with BRCA2 gene mutation can choose between BRRM or surveillance knowing that it makes little difference to whether or not they will die from breast cancer.

 However, they will still be at increased risk of developing the disease, and the treatment for it can be unpleasant and carries its own risks.

These findings are important because they help in individualized counseling regarding the difficult choice women with BRCA mutation face between BRRM and surveillance.

Many of the women want to retain their breast and they are willing to face the risk of developing breast cancer and undergoing essential treatment after diagnosis. Knowing the type of mutation, they carry, they may find some relief in knowing that ongoing intensive surveillance may be as good as BRRM when it comes to breast cancer-­specific survival if they have BRCA2 mutation.

Conference news release

Media: breast360.org

Related article: FDA approves first home-based testing for three BRCA mutations

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